U.S. patent application number 17/282358 was filed with the patent office on 2021-11-11 for crystalline forms of niraparib freebase.
The applicant listed for this patent is Tesaro, Inc.. Invention is credited to Alistair James Stewart, Yi Wang, George Wu, Jianguo Yin.
Application Number | 20210347758 17/282358 |
Document ID | / |
Family ID | 1000005796986 |
Filed Date | 2021-11-11 |
United States Patent
Application |
20210347758 |
Kind Code |
A1 |
Stewart; Alistair James ; et
al. |
November 11, 2021 |
Crystalline Forms of Niraparib Freebase
Abstract
Crystalline niraparib freebase is provided. Also provided are
pharmaceutical compositions comprising crystalline niraparib
freebase, and methods and uses pertaining to the same.
Inventors: |
Stewart; Alistair James;
(Waltham, MA) ; Wang; Yi; (Waltham, MA) ;
Wu; George; (Waltham, MA) ; Yin; Jianguo;
(Waltham, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Tesaro, Inc. |
Waltham |
MA |
US |
|
|
Family ID: |
1000005796986 |
Appl. No.: |
17/282358 |
Filed: |
October 3, 2019 |
PCT Filed: |
October 3, 2019 |
PCT NO: |
PCT/US2019/054533 |
371 Date: |
April 1, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62740869 |
Oct 3, 2018 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07B 2200/13 20130101;
C07D 401/10 20130101 |
International
Class: |
C07D 401/10 20060101
C07D401/10 |
Claims
1. A crystalline form of a
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
freebase.
2. The crystalline form according to claim 1, wherein the
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
freebase is characterized by an X-ray powder diffraction (XRPD)
pattern comprising at least three diffraction angles, when measured
using Cu K radiation, selected from a group consisting of about
12.2, 15.6, 16.5, 16.9, 18.7, 19.6, 21.6, 22.4, 22.5, 23.2, 25.2,
27.9, and 29.3 degrees 2.theta..
3. The crystalline form according to claim 1, wherein the
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
freebase is characterized by an X-ray powder diffraction (XRPD)
pattern comprising at least three diffraction angles, when measured
using Cu K radiation, selected from a group consisting of about
15.6, 16.5, 16.9, 18.7, 19.6, 21.6, 22.4, 22.5, 23.2, and 29.3
degrees 2.theta..
4. The crystalline form according to claim 1, wherein the
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
freebase is characterized by an X-ray powder diffraction (XRPD)
pattern comprising at least three diffraction angles, when measured
using Cu K radiation, selected from a group consisting of about
15.6, 16.5, 18.7, 19.6, 21.6, 22.4, 22.5, and 23.2 degrees
2.theta..
5. The crystalline form according to claim 1, wherein the
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
freebase is characterized by an X-ray powder diffraction (XRPD)
pattern, when measured using Cu K radiation, comprising diffraction
angles of about 15.6, 16.5, 16.9, 18.7, 19.6, 21.6, and 22.5
degrees 2.theta..
6. The crystalline form according to claim 1, wherein the
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
freebase is characterized by an X-ray powder diffraction (XRPD)
pattern, when measured using Cu K radiation, comprising diffraction
angles of about 18.7, 19.6, 21.6, and 22.5 degrees 2.theta..
7. The crystalline form according to claim 1, wherein the
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
freebase is characterized by an X-ray powder diffraction (XRPD)
pattern comprising diffraction angles with 2.theta. values, and
optional relative intensities, according to the following table:
TABLE-US-00016 Pos. [.degree.20] Rel. Int. [%] 8.4 3 12.2 8 12.8 1
13.7 1 15.6 19 16.5 25 16.9 27 17.4 7 18.0 2 18.7 100 19.6 37 20.0
7 21.6 28 22.4 23 22.5 38 23.2 21 24.4 2 25.0 6 25.2 9 25.7 6 27.3
2 27.9 8 29.3 13 30.4 2 31.0 3 32.0 2 32.7 1 33.2 3 33.8 3 34.7
2
8. The crystalline form according to claim 1, wherein the
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
freebase is characterised by an X-ray powder diffraction (XRPD)
pattern substantially in accordance with FIG. 1.
9. The crystalline form according to claim 1, characterised by
adsorbing less than about 1% by weight of water up to about 90%
relative humidity at about 25.degree. C.
10. The crystalline form according to claim 2, further comprising:
a crystalline Form II characterized by an X-ray powder diffraction
(XRPD) pattern substantially in accordance with FIG. 10; a
crystalline Form III characterized by an X-ray powder diffraction
(XRPD) pattern substantially in accordance with FIG. 11; a
crystalline Form IV characterized by an X-ray powder diffraction
(XRPD) pattern substantially in accordance with FIG. 14; and/or a
crystalline Form V characterized by an X-ray powder diffraction
(XRPD) pattern substantially in accordance with FIG. 15.
11. A composition comprising the crystalline form of claim 1,
wherein the composition is substantially free of amorphous
niraparib, a pharmaceutically acceptable salt of niraparib, and/or
any other solid form of niraparib or niraparib salt.
12. A composition comprising the crystalline form of claim 1,
wherein less than about 10% or less than about 5% of the total
niraparib in the composition is in the form of amorphous niraparib,
a pharmaceutically acceptable salt of niraparib, and/or any other
solid form of niraparib or niraparib salt.
13. A pharmaceutical composition comprising the crystalline form of
claim 1, or the composition of claim 11, and at least one
pharmaceutically acceptable excipient.
14.-15. (canceled)
16. A method of treating cancer, stroke, autoimmune diabetes, a
neurological disease, an inflammatory disease, a metabolic disease
or a cardiovascular disease in a subject, the method comprising
administering to the subject an effective amount of the crystalline
niraparib freebase of claim 1, or the composition of claim 11.
17. The method according to claim 16, wherein the method is a
method of treating cancer.
18. The method according to claim 17, wherein the cancer is
associated with BRCA1 and/or BRCA2 mutations.
19. The method according to claim 17, wherein the cancer is
associated with a mutation in ATM, ATR, BAP1, BARD1, BLM, BRIP1,
MRE11A, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, RAD52, RAD54L,
XRCC2, or any combinations thereof.
20. The method according to claim 17, wherein the cancer is
epithelial ovarian cancer, fallopian tube cancer, or primary
peritoneal cancer.
21.-22. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims benefit of U.S. Provisional
Application No. 62/740,869, filed Oct. 3, 2018, which is hereby
incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] This disclosure relates to crystalline niraparib, to
compositions comprising crystalline niraparib, and to uses of the
same.
SUMMARY OF THE INVENTION
[0003] Niraparib is the international nonproprietory name for
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. The
compound has the structure
##STR00001##
and it is a potent inhibitor of poly (ADP-ribose) polymerase
("PARP") proteins, in particular being selective for PARP-1 and
PARP-2 (see e.g. Thorsell et al., J. Med. Chem. (2017)
60:1262-1271).
[0004] Niraparib inhibits the proliferation of BRCA1- and
BRCA2-deficient cell lines in vitro. Niraparib decreases tumor
growth in mouse xenograft models of human cancers with deficiencies
in BRCA1 and BRCA2 or with homologous recombination deficiency
(HRD) that have either mutated or wild-type BRCA1/2. Niraparib also
can be useful in treating cancers characterized a deficiency in
certain genes involved in the homologous recombination repair (HRR)
pathway, including non-BRCA1/2 HRR genes. Niraparib can form
PARP-DNA complexes resulting in DNA damage, apoptosis, and cell
death (Murai et al., Cancer Res. (2012) 72:5588-99). Niraparib also
has pharmacologic activity on dopamine, norepinephrine and
serotonin transporters at concentrations similar to those which are
effective for PARP inhibition (see e.g. Ison et al., Clinical
Cancer Research (2018) 24(17):4066-4071). Niraparib therefore has
the potential to treat conditions including cancers (especially
cancers which are refractory to platinum-based chemotherapy), as
well as conditions such as stroke, autoimmune diabetes,
neurological diseases, inflammatory diseases, metabolic diseases
and cardiovascular diseases.
[0005] The discovery of niraparib and its activity as a PARP
inhibitor is reported by Jones et al. (J. Med. Chem., 2009,
52:7170-7185). Jones et al. describe a synthesis of niraparib in
which the freebase form of the compound is obtained as a
lyophilised powder.
[0006] Amorphous niraparib freebase is poorly soluble in water
(around 1 mg/mL) and its solubility does not improve greatly at
lower pH values. Typically, organic compounds are more readily
soluble when in an amorphous state than when in a crystalline
state. Surprisingly, however, the present inventors have discovered
that niraparib freebase can be obtained in crystalline form,
wherein the crystalline form has a similar or an increased
solubility relative to the amorphous form. Crystalline niraparib
freebase has other desirable properties, including a good stability
and a lack of hygroscopicity.
[0007] Accordingly, the present invention relates to crystalline
niraparib freebase, and to compositions and uses of the same. The
present invention meets a need for new forms of niraparib having
desirable properties for pharmaceutical formulation (e.g. into oral
dosage forms), such as e.g. improved physicochemical and/or
pharmacokinetic properties.
[0008] In a first aspect, the invention provides a crystalline form
of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase.
[0009] In other aspects and embodiments, the invention provides a
crystalline Form I of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase.
[0010] In embodiments, a crystalline form of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase has an X-ray powder diffraction (XRPD) pattern
comprising at least three diffraction angles, when measured using
Cu K radiation, selected from a group consisting of about 12.2,
15.6, 16.5, 16.9, 18.7, 19.6, 21.6, 22.4, 22.5, 23.2, 25.2, 27.9,
and 29.3 degrees 2.theta..
[0011] In embodiments, a crystalline form of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase has an X-ray powder diffraction (XRPD) pattern
comprising at least three diffraction angles, when measured using
Cu K radiation, selected from a group consisting of about 15.6,
16.5, 16.9, 18.7, 19.6, 21.6, 22.4, 22.5, 23.2, and 29.3 degrees
2.theta..
[0012] In embodiments, a crystalline form of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase has an X-ray powder diffraction (XRPD) pattern
comprising at least three diffraction angles, when measured using
Cu K radiation, selected from a group consisting of about 15.6,
16.5, 18.7, 19.6, 21.6, 22.4, 22.5, and 23.2 degrees 2.theta..
[0013] In embodiments, a crystalline form of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase has an XRPD pattern, when measured using Cu K
radiation, comprising diffraction angles of about 15.6, 16.5, 16.9,
18.7, 19.6, 21.6, and 22.5 degrees 2.theta..
[0014] In embodiments, a crystalline form of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase has an X-ray powder diffraction (XRPD)
pattern, when measured using Cu K radiation, comprising diffraction
angles of about 18.7, 19.6, 21.6, and 22.5 degrees 2.theta..
[0015] In embodiments, a crystalline form (crystalline Form I) of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase has an X-ray powder diffraction (XRPD) pattern
comprising a diffraction angle at 18.7.+-.0.2.degree. 2.theta..
[0016] In embodiments, a crystalline form (crystalline Form I) of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase has an XRPD pattern comprising diffraction
angles at 18.7 and 22.5.+-.0.2.degree. 2.theta..
[0017] In embodiments, a crystalline form (crystalline Form I) of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase has an XRPD pattern comprising diffraction
angles at 18.7 and 19.6.+-.0.2.degree. 2.theta..
[0018] In embodiments, a crystalline form (crystalline Form I) of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase has an XRPD pattern comprising diffraction
angles at 18.7, 19.6 and 22.5.+-.0.2.degree. 2.theta..
[0019] In embodiments, a crystalline form (crystalline Form I) of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase has an XRPD pattern comprising one or more
diffraction angles at 16.9, 18.7, 19.6, 21.6 and
22.5.+-.0.2.degree. 2.theta..
[0020] In embodiments a crystalline form (crystalline Form I) of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase has an XRPD pattern comprising at least two
diffraction angles at 16.9, 18.7, 19.6, 21.6 and
22.5.+-.0.2.degree. 2.theta..
[0021] In embodiments, a crystalline form (crystalline Form I) of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase has an XRPD pattern comprising at least three
diffraction angles at 16.9, 18.7, 19.6, 21.6 and
22.5.+-.0.2.degree. 2.theta..
[0022] In embodiments, a crystalline form (crystalline Form I) of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase has an XRPD pattern comprising at least four
diffraction angles at 16.9, 18.7, 19.6, 21.6 and
22.5.+-.0.2.degree. 2.theta..
[0023] In embodiments, a crystalline form (crystalline Form I) of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase has an XRPD pattern comprising diffraction
angles at 16.9, 18.7, 19.6, 21.6 and 22.5.+-.0.2.degree.
2.theta..
[0024] In embodiments, a crystalline form (crystalline Form I) of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase has an XRPD pattern comprising one or more
diffraction angles at 15.6, 16.5, 22.4, 23.2, and
29.3.+-.0.2.degree. 2.theta..
[0025] In embodiments, a crystalline form (crystalline Form I) of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase has an XRPD pattern comprising at least two
diffraction angles at 15.6, 16.5, 22.4, 23.2, and
29.3.+-.0.2.degree. 2.theta..
[0026] In embodiments, a crystalline form (crystalline Form I) of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase has an XRPD pattern comprising at least three
diffraction angles at 15.6, 16.5, 22.4, 23.2, and
29.3.+-.0.2.degree. 2.theta..
[0027] In embodiments, a crystalline form (crystalline Form I) of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase has an XRPD pattern comprising at least four
diffraction angles at 15.6, 16.5, 22.4, 23.2, and/or
29.3.+-.0.2.degree. 2.theta..
[0028] In embodiments, a crystalline form (crystalline Form I) of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase has an XRPD pattern comprising diffraction
angles at 15.6, 16.5, 22.4, 23.2, and 29.3.+-.0.2.degree.
2.theta..
[0029] In embodiments, a crystalline form (crystalline Form I) of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase has an XRPD pattern comprising diffraction
angles at 15.6, 16.5, 16.9, 18.7, 19.6, 21.6, 22.4, 22.5, 23.2 and
29.3.+-.0.2.degree. 2.theta..
[0030] In embodiments, a crystalline form (crystalline Form I) of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase has an XRPD pattern comprising diffraction
angles with the 2.theta. values, and optionally also relative
intensities, according to the following table:
TABLE-US-00001 Pos. [.degree.2.theta.] Rel. Int. [%] 8.4 3 12.2 8
12.8 1 13.7 1 15.6 19 16.5 25 16.9 27 17.4 7 18.0 2 18.7 100 19.6
37 20.0 7 21.6 28 22.4 23 22.5 38 23.2 21 24.4 2 25.0 6 25.2 9 25.7
6 27.3 2 27.9 8 29.3 13 30.4 2 31.0 3 32.0 2 32.7 1 33.2 3 33.8 3
34.7 2
[0031] In embodiments, a crystalline form (crystalline Form I) of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase is characterised by an XRPD pattern
substantially as shown in FIG. 1.
[0032] In embodiments, a crystalline form (crystalline Form I) of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase is characterised by an infrared (IR) spectrum
comprising a peak at about 1652 cm.sup.-1 and a peak at about 1608
cm.sup.1.
[0033] In embodiments, a crystalline form (crystalline Form I) of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase is characterised by an infrared (IR) spectrum
substantially as shown in FIG. 4.
[0034] In embodiments, a crystalline form (crystalline Form I) of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase is characterised by a Raman spectrum
comprising peaks at about 960.3, 1457.5 and 1607.0 cm.sup.-1.
[0035] In embodiments, a crystalline form (crystalline Form I) of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase is characterised by a Raman spectrum
substantially as shown in FIG. 5.
[0036] In embodiments, a crystalline form (crystalline Form I) of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase is characterised by a melting point of about
185-195.degree. C.
[0037] In embodiments, a crystalline form (crystalline Form I) of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase is characterised by a DTA thermogram
substantially as shown in FIG. 6.
[0038] In embodiments, a crystalline form (crystalline Form I) of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase is characterised by a DSC thermogram
substantially as shown in FIG. 7.
[0039] In embodiments, a crystalline form (crystalline Form I) of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase is characterised by adsorbing less than about
1% by weight of water up to about 90% relative humidity at about
25.degree. C.
[0040] In other aspects and embodiments, the invention provides a
crystalline Form II, III, IV, or V of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase.
[0041] In other aspects, the invention provides a composition
comprising a crystalline niraparib freebase defined hereinbefore,
wherein the composition is substantially free of amorphous
niraparib, a pharmaceutically acceptable salt of niraparib, and/or
any other solid form of niraparib or niraparib salt.
[0042] In embodiments, less than about 10% or less than about 5% of
the total niraparib in the composition is in the form of said
amorphous niraparib, said pharmaceutically acceptable salt of
niraparib, and/or any other solid form of niraparib or niraparib
salt.
[0043] In other aspects, the invention provides a pharmaceutical
composition comprising a crystalline niraparib freebase defined
hereinbefore, and at least one pharmaceutically acceptable
excipient.
[0044] In other aspects, the invention provides the crystalline
niraparib freebase, the composition, or the pharmaceutical
composition defined hereinbefore, for use in therapy.
[0045] In other aspects, the invention provides use of the
crystalline niraparib freebase, or the pharmaceutical composition
defined hereinbefore, in the manufacture of a medicament.
[0046] In other aspects, the invention provides a method of
treating cancer, stroke, autoimmune diabetes, a neurological
disease, an inflammatory disease, a metabolic disease or a
cardiovascular disease in a subject, the method comprising
administering to the subject an effective amount of the crystalline
niraparib freebase, or the composition, or the pharmaceutical
composition defined hereinbefore.
[0047] In embodiments, the method is a method of treating
cancer.
[0048] In embodiments, said cancer is associated with BRCA1 and/or
BRCA2 mutations.
[0049] In embodiments, said cancer is association with a mutation
in ATM, ATR, BAP1, BARD1, BLM, BRIP1, MRE11A, NBN, PALB2, RAD51,
RAD51B, RAD51C, RAD51D, RAD52, RAD54L, or XRCC2, or any combination
thereof.
[0050] In embodiments, said cancer is epithelial ovarian cancer,
fallopian tube cancer, or primary peritoneal cancer.
[0051] In other aspects, the invention provides the crystalline
niraparib freebase, or the composition, or the pharmaceutical
composition defined hereinbefore, for use in a method as defined
hereinbefore.
[0052] In other aspects, the invention provides use of the
crystalline niraparib freebase, or the composition, or the
pharmaceutical composition defined hereinbefore, in the manufacture
of a medicament for use in a method as defined hereinbefore.
BRIEF DESCRIPTION OF THE FIGURES
[0053] FIG. 1 shows an XRPD pattern of niraparib freebase Form I
prepared according to the present Examples.
[0054] FIG. 2 shows photomicrographs of niraparib freebase Form I
prepared according to the present Examples. These are obtained
under standard (FIGS. 2A and 2B) and polarised light (FIGS. 2C and
2D) conditions.
[0055] FIG. 3 shows SEM images of niraparib freebase Form I
crystals prepared according to the present Examples at various
levels of magnification.
[0056] FIG. 4 shows an FT-IR spectrum of niraparib freebase Form I
prepared according to the present Examples.
[0057] FIG. 5 shows a Raman spectrum of niraparib freebase Form I
(.lamda..sub.ex=785 nm) prepared according to the present
Examples.
[0058] FIG. 6 shows TG/DTA thermograms of niraparib freebase Form I
prepared according to the present Examples.
[0059] FIG. 7 shows a DSC thermogram of niraparib freebase Form I
prepared according to the present Examples.
[0060] FIG. 8 shows a GVS isotherm plot of niraparib freebase Form
I prepared according to the present Examples. The figure overlays
two full sorption/desorption cycles. The solid line with empty
circular markers shows sorption #1 (40% to 90% RH) and the dashed
line with filled diamond markers shows desorption #1 (90% to 0%
RH). The solid line with empty triangular markers shows sorption #2
(0% to 90% RH) and the dashed line with filled square markers shows
desorption #2 (90% to 0% RH). The solid line with asterisk markers
shows sorption #3 (0% to 40% RH).
[0061] FIG. 9 shows the XRPD pattern of amorphous niraparib
freebase prepared according to the present Examples.
[0062] FIG. 10 shows an XRPD pattern of niraparib freebase Form II
prepared according to the present Examples.
[0063] FIG. 11 shows an XRPD pattern of niraparib freebase Form III
prepared according to the present Examples.
[0064] FIG. 12 shows a DSC thermogram in which a previously-heated
and cooled sample of niraparib freebase is re-heated.
[0065] FIG. 13 shows an overlay of XRPD patterns of niraparib
freebase Form I (top) versus amorphous niraparib freebase (bottom)
obtained by melting and cooling (VT-XRPD).
[0066] FIG. 14 shows an overlay of XRPD patterns obtained by
reheating a cooled sample of niraparib freebase (VT-XRPD). The top
scan shows the XRPD pattern of the initial, cool material. The
second scan shows the onset of recrystallization to Form IV at
.about.122.degree. C. The third scan shows the change in XRPD
pattern at the onset of melting at .about.168.degree. C. The bottom
scan shows the pattern at 200.degree. C., after melting.
[0067] FIG. 15 shows the XRPD pattern of niraparib freebase Form V
prepared according to the present Examples.
[0068] FIG. 16 shows an overlay of the .sup.1H-NMR spectra of
crystalline niraparib Form I (upper trace) and Form IV (lower
trace) prepared according to the present Examples.
DETAILED DESCRIPTION
[0069] Although specific embodiments of the present disclosure will
now be described with reference to the description and examples, it
should be understood that such embodiments are by way of example
only and merely illustrative of but a small number of the many
possible specific embodiments which can represent applications of
the principles of the present disclosure. Various changes and
modifications will be obvious to those of skill in the art given
the benefit of the present disclosure and are deemed to be within
the spirit and scope of the present disclosure as further defined
in the appended claims.
Definitions
[0070] Unless defined otherwise, all technical and scientific terms
used herein have the same meanings as commonly understood by one of
ordinary skill in the art to which this disclosure belongs.
Although any methods and materials similar or equivalent to those
described herein can be used in the practice or testing of the
present invention, exemplary methods, devices, and materials are
now described. All technical and patent publications cited herein
are incorporated herein by reference in their entirety. Nothing
herein is to be construed as an admission that the invention is not
entitled to antedate such disclosure by virtue of prior
invention.
[0071] The practice of the present disclosure will employ, unless
otherwise indicated, conventional techniques of chemical synthesis,
tissue culture, immunology, molecular biology, microbiology, cell
biology and recombinant DNA, which are within the skill of the art.
See, e.g., Michael R. Green and Joseph Sambrook, Molecular Cloning
(4.sup.th ed., Cold Spring Harbor Laboratory Press 2012.
[0072] Numerical designations, e.g. pH, temperature, time,
concentration, molecular weight, etc., including ranges, are
approximations which are varied (+) or (-) by increments of 0.1 or
1.0, where appropriate. It is to be understood, although not always
explicitly stated that all numerical designations are preceded by
the term "about". It also is to be understood, although not always
explicitly stated, that the reagents described herein are merely
exemplary and that equivalents of such may be known in the art.
[0073] As used in the specification and claims, the singular forms
"a", "an" and "the" include plural references unless the context
clearly dictates otherwise. For example, the term "a cell" includes
a plurality of cells, including mixtures thereof. Unless
specifically stated or obvious from context, as used herein, the
term "or" is understood to be inclusive. The term "including" is
used herein to mean, and is used interchangeably with, the phrase
"including but not limited to".
[0074] As used herein, and unless otherwise specified, the terms
"about" and "approximately", when used in connection with doses,
amounts, or weight percent of ingredients of a composition or a
dosage form, mean a dose, amount, or weight percent that is
recognized by those of ordinary skill in the art to provide a
pharmacological effect equivalent to that obtained from the
specified dose, amount, or weight percent. Specifically, the terms
"about" and "approximately", when used in this context, contemplate
a dose, amount, or weight percent within 15%, more specifically
within 10%, more specifically within 5%, of the specified dose,
amount, or weight percent. As used herein, and unless otherwise
specified, the terms "about" and "approximately", when used in
connection with a numeric value or range of values which is
provided to characterize a particular solid form, e.g., a specific
temperature or temperature range, such as, for example, that
describing a melting, dehydration, desolvation or glass transition
temperature; a mass change, such as, for example, a mass change as
a function of temperature or humidity; a solvent or water content,
in terms of, for example, mass or a percentage; or a peak position
or diffraction angle, such as, for example, in analysis by IR or
Raman spectroscopy or XRPD; indicate that the value or range of
values may deviate to an extent deemed reasonable to one of
ordinary skill in the art while still describing the particular
solid form. Specifically, the terms "about" and "approximately",
when used in this context, indicate that the numeric value or range
of values may vary, in particular embodiments, within 20%, 10%, 9%,
8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the recited
value or range of values. With respect to XRPD, values given are
.+-.0.2 degrees 2.theta. if not expressly specified as such.
[0075] As used herein, the term "comprising" or "comprises" is
intended to mean that the compositions and methods include the
recited elements, but not excluding others. "Consisting essentially
of" when used to define compositions and methods, shall mean
excluding other elements of any essential significance to the
combination for the stated purpose. Thus, a composition consisting
essentially of the elements as defined herein would not exclude
contaminants from the isolation and purification method and
pharmaceutically acceptable carriers, such as phosphate buffered
saline, preservatives and the like. "Consisting of" shall mean
excluding more than trace elements of other ingredients and
substantial method steps for administering the compositions of this
disclosure or process steps to produce a composition or achieve an
intended result. Embodiments defined by each of these transition
terms are within the scope of this invention. Use of the term
"comprising" herein is intended to encompass, and to disclose, the
corresponding statements in which the term "comprising" is replaced
by "consisting essentially of" or "consisting of".
[0076] A "subject", "individual" or "patient" is used
interchangeably herein, and refers to a vertebrate, such as a
mammal. Mammals include, but are not limited to, rodents, farm
animals, sport animals, pets and primates; for example murines,
rats, rabbit, simians, bovines, ovines, porcines, canines, felines,
equines, and humans. In one embodiment, the mammals include horses,
dogs, and cats. In a preferred embodiment, the mammal is a
human.
[0077] "Administering" is defined herein as a means of providing an
agent or a composition containing the agent to a subject in a
manner that results in the agent being inside the subject's body.
Such an administration can be by any route including, without
limitation, oral, transdermal (e.g. by the vagina, rectum, or oral
mucosa), by injection (e.g. subcutaneous, intravenous, parenteral,
intraperitoneal, or into the central nervous system), or by
inhalation (e.g. oral or nasal). Pharmaceutical preparations are,
of course, given by forms suitable for each administration
route.
[0078] "Treating" or "treatment" of a disease includes: (1)
preventing the disease, i.e. causing the clinical symptoms of the
disease not to develop in a patient that may be predisposed to the
disease but does not yet experience or display symptoms of the
disease; (2) inhibiting the disease, i.e. arresting or reducing the
development of the disease or its clinical symptoms; and/or (3)
relieving the disease, i.e. causing regression of the disease or
its clinical symptoms.
[0079] The term "suffering" as it relates to the term "treatment"
refers to a patient or individual who has been diagnosed with or is
predisposed to the disease. A patient may also be referred to being
"at risk of suffering" from a disease because of a history of
disease in their family lineage or because of the presence of
genetic mutations associated with the disease. A patient at risk of
a disease has not yet developed all or some of the characteristic
pathologies of the disease.
[0080] An "effective amount" or "therapeutically effective amount"
is an amount sufficient to effect beneficial or desired results. An
effective amount can be administered in one or more
administrations, applications or dosages. Such delivery is
dependent on a number of variables including the time period for
which the individual dosage unit is to be used, the bioavailability
of the therapeutic agent, the route of administration, etc. It is
understood, however, that specific dose levels of the therapeutic
agents of the present invention for any particular subject depends
upon a variety of factors including, for example, the activity of
the specific compound employed, the age, body weight, general
health, sex, and diet of the subject, the time of administration,
the rate of excretion, the drug combination, and the severity of
the particular disorder being treated and form of administration.
Treatment dosages generally may be titrated to optimize safety and
efficacy. Typically, dosage-effect relationships from in vitro
and/or in vivo tests initially can provide useful guidance on the
proper doses for patient administration. In general, one will
desire to administer an amount of the compound that is effective to
achieve a serum level commensurate with the concentrations found to
be effective in vitro. Determination of these parameters is well
within the skill of the art. These considerations, as well as
effective formulations and administration procedures are well known
in the art and are described in standard textbooks.
[0081] As used herein, the term "pharmaceutically acceptable
excipient" encompasses any of the standard pharmaceutical
excipients, including carriers such as a phosphate buffered saline
solution, water, and emulsions, such as an oil/water or water/oil
emulsion, and various types of wetting agents. Pharmaceutical
compositions also can include other components such as stabilizers
and preservatives. For examples of carriers, stabilizers and
adjuvants, see Remington's Pharmaceutical Sciences (20th ed., Mack
Publishing Co. 2000).
[0082] The term "freebase" is generally used herein to mean
niraparib (when in a solid, e.g. crystalline, state) which is
substantially free of counter-ionic species. Thus, in solid
niraparib freebase, the niraparib is substantially in a
non-ionized, i.e. neutral, form. The niraparib freebase of the
present disclosure is typically at least 90% in a non-ionized form,
preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%
in a non-ionized form, e.g. essentially 100% in a non-ionized
form.
[0083] The term "amorphous", "amorphous form", and related terms
used herein mean that the substance, component or product in
question is not substantially crystalline as determined by X-ray
diffraction. In certain embodiments, a sample comprising an
amorphous form of a substance may be substantially free of other
amorphous forms and/or crystal forms.
[0084] The term "crystalline" and related terms used herein, when
used to describe a substance, component, product, or form, means
that the substance, component or product is substantially
crystalline as determined by X-ray diffraction (see e.g.
Remington's Pharmaceutical Sciences, 22nd ed., Pharmaceutical
Press, 2012; and The United States Pharmacopoeia, 30th ed.,
2011).
[0085] The term "crystal form", "crystalline form" and related
terms herein refer to a crystalline solid form comprising a
chemical compound, and may refer to a particular single-component
or multiple-component crystal form, including, but not limited to,
a polymorph, a solvate, a hydrate or other molecular complex.
[0086] The terms "polymorphs", "polymorphic forms" and related
terms herein refer to two or more crystal forms that comprise the
same molecule, molecules or ions. Different polymorphs may have
different physical properties such as, for example, melting
temperatures, heats of fusion, solubilities, dissolution rates
and/or vibrational spectra as a result of the arrangement or
conformation of the molecules or ions in the crystal lattice. The
differences in physical properties exhibited by polymorphs may
affect pharmaceutical parameters such as storage stability,
compressibility and density (which can be important in formulation
and product manufacturing), and dissolution rate (which can be an
important factor in bioavailability). Differences in stability can
result from changes in chemical reactivity (e.g. differential
oxidation, such that a dosage form discolors more rapidly when
comprised of one polymorph than when comprised of another
polymorph) or mechanical changes (e.g. tablets crumble on storage
as a kinetically favored polymorph converts to thermodynamically
more stable polymorph) or both (e.g. tablets of one polymorph are
more susceptible to breakdown at high humidity). As a result of
solubility/dissolution differences, in the extreme case, some
polymorphic transitions may result in variations in potency or lack
of potency, or variations in toxicity, which may result in higher
or lower incidence of unwanted side effects or a change in severity
of an unwanted side effect. In addition, the physical properties of
the crystal may be important in processing; for example, one
polymorph might be more likely to form solvates or might be
difficult to filter and wash free of impurities (e.g. particle
shape and size distribution might be different between
polymorphs).
[0087] Techniques for characterizing crystal forms and amorphous
forms include, but are not limited to, thermal gravimetric analysis
(TGA), melting point, differential scanning calorimetry (DSC),
X-ray powder diffractometry (XRPD), single-crystal X-ray
diffractometry, vibrational spectroscopy, e.g. infrared (IR) and
Raman spectroscopy, solid-state and solution nuclear magnetic
resonance (NMR) spectroscopy, optical microscopy (e.g. polaraized
light microscopy), hot stage optical microscopy, scanning electron
microscopy (SEM), electron crystallography, dynamic vapor sorption
(DVS), and quantitative analysis, particle size analysis (PSA),
surface area analysis, solubility studies and dissolution studies.
Exemplary experimental values described herein may be variable
according to the standard measures of the field, such as the
exemplary variation described herein.
[0088] Where a crystalline form is characterized by one or more
XRPD diffraction angles, and unless otherwise indicated, it is to
be understood that the XRPD pattern is obtained under standard
conditions (e.g. as described herein) and that the 2.theta. values
may be variable according to the standard measures in the field.
For example, 2.theta. values recited herein may be variable by
.+-.0.2.degree.. Furthermore, where a crystalline form is
characterized by one or more specified XRPD diffraction angles,
those diffraction angles will typically represent diffraction
angles having a relative intensity within the diffractogram of at
least 1%, e.g. of at least 2%, 5% or 10% relative intensity.
[0089] The recitation of an embodiment for a variable or aspect
herein includes that embodiment as any single embodiment or in
combination with any other embodiments or portions thereof.
[0090] Compositions and methods provided herein may be combined
with one or more of any of the other compositions and methods
provided herein.
[0091] The following abbreviations are used herein: [0092] .degree.
C.=Celsius [0093] DMSO=dimethyl sulfoxide [0094] DTA=differential
thermal analysis [0095] DSC=differential scanning calorimetry
[0096] GC=gas chromatography [0097] h=hour [0098] HPLC=high
pressure liquid chromatography [0099] HRD=homologous recombination
deficiency [0100] Hz=hertz [0101] MEK=methyl ethyl ketone [0102]
2-MeTHF=2-methyltetrahydrofuran [0103] MHz=megahertz; [0104]
min=minute [0105] MS=mass spectrometry [0106] NMR=nuclear magnetic
resonance [0107] PARP=poly (ADP-ribose) polymerase [0108]
rt/RT=room temperature [0109] TBME=tert-butyl methyl ether [0110]
TGA=thermogravimetric analysis [0111] (VT-)XRPD=(variable
temperature) X-ray power diffraction
Crystalline Niraparib Freebase
[0112] The present invention relates to the drug niraparib in a new
physical form (crystalline freebase) having desirable properties
for pharmaceutical formulation, such as e.g. improved
physicochemical and/or pharmacokinetic properties. The use of
niraparib in its freebase form also allows for increased drug
loading possibilities relative to other forms. For example,
relative to a salt form of niraparib, the drug loading of a
niraparib freebase dosage form could be increased by at least
around 40%. Such an increased drug loading could translate into a
reduced unit dosage size and/or a reduced pill burden for a subject
who receives the dosage form, both of which are desirable outcomes
from a pharmaceutical perspective.
[0113] In a first aspect, therefore, the present invention provides
a crystalline form of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib)freebase.
[0114] In one embodiment, the crystalline
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase comprises Form I, Form II, Form III, Form IV
and/or Form V crystalline niraparib freebase, e.g. as characterised
herein. In another embodiment, the crystalline niraparib freebase
is substantially free from Form II, Form III, Form IV and/or Form V
crystalline niraparib freebase, e.g. as characterised herein.
[0115] Exemplary crystalline forms are described herein. Exemplary
X-ray powder diffraction (XRPD) patterns are also described herein.
In embodiments, an XRPD pattern is measured using Cu K radiation.
In embodiments, an XRPD pattern is characterized by certain
diffraction angles (peaks) as described herein.
Form I Crystalline Niraparib Freebase
[0116] In one embodiment, the crystalline
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib)freebase comprises Form I crystalline niraparib
freebase, e.g. as characterised herein. Viewed from this aspect,
the invention provides a crystalline Form I of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase.
[0117] The crystalline niraparib freebase may be characterised by
one or more (e.g. one, two, three, four or five) XRPD diffraction
angles at 2.theta. values of 16.9.degree., 18.7.degree.,
19.6.degree., 21.6.degree. and 22.5.degree.. In embodiments, the
crystalline niraparib freebase is characterised by at least two
XRPD diffraction angles at 2.theta. values of 16.9.degree.,
18.7.degree., 19.6.degree., 21.6.degree. and 22.5.degree.. In
embodiments, the crystalline niraparib freebase is characterised by
at least three XRPD diffraction angles at 2.theta. values of
16.9.degree., 18.7.degree., 19.6.degree., 21.6.degree. and
22.5.degree.. In embodiments, the crystalline niraparib freebase is
characterised by at least four XRPD diffraction angles at 2.theta.
values of 16.9.degree., 18.7.degree., 19.6.degree., 21.6.degree.
and 22.5.degree.. In embodiments, the crystalline niraparib
freebase is characterised by XRPD diffraction angles at 2.theta.
values of 16.9.degree., 18.7.degree., 19.6.degree., 21.6.degree.
and 22.5.degree.. In embodiments, the crystalline niraparib
freebase is characterised by (e.g. further characterised by) one or
more (e.g. one, two, three, four or five) XRPD diffraction angles
at 2.theta. values of 15.6.degree., 16.5.degree., 22.4.degree.,
23.2.degree., and 29.3.degree.. In embodiments, the crystalline
niraparib freebase is characterised by at least two XRPD
diffraction angles at 2.theta. values of 15.6.degree.,
16.5.degree., 22.4.degree., 23.2.degree., and 29.3.degree.. In
embodiments, the crystalline niraparib freebase is characterised by
at least three XRPD diffraction angles at 2.theta. values of
15.6.degree., 16.5.degree., 22.4.degree., 23.2.degree., and
29.3.degree.. In embodiments, the crystalline niraparib freebase is
characterised by at least four XRPD diffraction angles at 2.theta.
values of 15.6.degree., 16.5.degree., 22.4.degree., 23.2.degree.,
and 29.3.degree.. In embodiments, the crystalline niraparib
freebase is characterised by XRPD diffraction angles at 2.theta.
values of 15.6.degree., 16.5.degree., 22.4.degree., 23.2.degree.,
and 29.3.degree..
[0118] In one embodiment, the crystalline niraparib freebase is
characterised by an XRPD diffraction angle at a 2.theta. value of
18.7.degree., and is optionally further characterised by one or
more XRPD diffraction angles e.g. at 2.theta. values of
22.5.degree., 19.6.degree., 21.6.degree., 16.9.degree.,
16.5.degree., 22.4.degree., 23.2.degree., 15.6.degree. and
29.32.degree.. Thus, the crystalline niraparib freebase may be
characterised by one, two, three, four, five, six, seven, eight,
nine or ten diffraction angles at 2.theta. values of 18.7.degree.,
22.5.degree., 19.6.degree., 21.6.degree., 16.9.degree.,
16.5.degree., 22.4.degree., 23.2.degree., 15.6.degree. and
29.3.degree.. In embodiments, the crystalline niraparib freebase is
characterised by XRPD diffraction angles at 2.theta. values of
15.6.degree., 16.5.degree., 16.9.degree., 18.7.degree.,
19.6.degree., 21.6.degree., 22.4.degree., 22.5.degree.,
23.2.degree. and 29.3.degree..
[0119] In one embodiment, the crystalline niraparib freebase is
characterised by XRPD diffraction angles at 2.theta. values of
18.7.degree. and 22.5.degree.. In another embodiment, the
crystalline niraparib freebase is characterised by XRPD diffraction
angles at 2.theta. values of 18.7.degree. and 19.6.degree.. In yet
another embodiment, the crystalline niraparib freebase is
characterised by XRPD diffraction angles at 2.theta. values of
18.7.degree., 22.5.degree., and 19.6.degree.. In a further
embodiment, the crystalline niraparib freebase is characterised by
XRPD diffraction angles at 18.7.degree. and 22.50, as well as one,
two, three, four, five, six or seven of 19.6.degree., 21.6.degree.,
16.9.degree., 16.5.degree., 22.4.degree., 23.3.degree. and
15.6.degree.. In a further embodiment, the crystalline niraparib
freebase is characterised by XRPD diffraction angles at
18.7.degree. and 19.6.degree., as well as one, two, three, four,
five, six or seven of 22.5.degree., 21.6.degree., 16.9.degree.,
16.5.degree., 22.4.degree., 23.2.degree. and 15.6.degree.. In a
further embodiment, the crystalline niraparib freebase is
characterised by XRPD diffraction angles at 18.7.degree.,
22.5.degree., and 19.6.degree., as well as one, two, three, four,
five or six of 21.6.degree., 16.9.degree., 16.5.degree.,
22.4.degree., 23.2.degree. and 15.6.degree.. In a further
embodiment, the crystalline niraparib freebase is characterised by
XRPD diffraction angles at 2.theta. values of 16.9.degree.,
18.7.degree., 19.6.degree., 21.6.degree. and 22.5.degree.. In a yet
further embodiment, the crystalline niraparib freebase is
characterised by XRPD diffraction angles at 2.theta. values of
15.6.degree., 16.5.degree., 16.9.degree., 18.7.degree.,
19.6.degree., 21.6.degree., 22.4.degree., 22.5.degree.,
23.2.degree. and 29.3.degree..
[0120] In one embodiment, the crystalline niraparib freebase is
characterised by one or more (e.g. one, two, three, four or five)
XRPD diffraction angles at 2.theta. values of 15.6.degree.,
16.5.degree., 23.2.degree., 25.2.degree. and 27.9.degree.. In
embodiments, the crystalline niraparib freebase is characterised by
at least two XRPD diffraction angles at 2.theta. values of
15.6.degree., 16.5.degree., 23.2.degree., 25.2.degree. and
27.9.degree.. In embodiments, the crystalline niraparib freebase is
characterised by at least three XRPD diffraction angles at 2.theta.
values of 15.6.degree., 16.5.degree., 23.2.degree., 25.2.degree.
and 27.9.degree.. In embodiments, the crystalline niraparib
freebase is characterised by at least four XRPD diffraction angles
at 2.theta. values of 15.6.degree., 16.5.degree., 23.2.degree.,
25.2.degree. and 27.9.degree.. In embodiments, the crystalline
niraparib freebase is characterised by XRPD diffraction angles at
2.theta. values of 15.6.degree., 16.5.degree., 23.2.degree.,
25.2.degree. and 27.9.degree.. In embodiments, the crystalline
niraparib freebase is characterised by an XRPD diffraction angle at
a 2.theta. value of 18.7.degree., and is further characterised by
one or more (e.g. one, two, three, four or five) XRPD diffraction
angles at 2.theta. values of 15.6.degree., 16.5.degree.,
23.2.degree., 25.2.degree. and 27.9.degree..
[0121] In embodiments, a crystalline form of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase has an X-ray powder diffraction (XRPD) pattern
comprising at least three diffraction angles, when measured using
Cu K radiation, selected from a group consisting of about 12.2,
15.6, 16.5, 16.9, 18.7, 19.6, 21.6, 22.4, 22.5, 23.2, 25.2, 27.9,
and 29.3 degrees 2.theta..
[0122] In embodiments, a crystalline form of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase has an X-ray powder diffraction (XRPD) pattern
comprising at least three diffraction angles, when measured using
Cu K radiation, selected from a group consisting of about 15.6,
16.5, 16.9, 18.7, 19.6, 21.6, 22.4, 22.5, 23.2, and 29.3 degrees
2.theta..
[0123] In embodiments, a crystalline form of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase has an X-ray powder diffraction (XRPD) pattern
comprising at least three diffraction angles, when measured using
Cu K radiation, selected from a group consisting of about 15.6,
16.5, 18.7, 19.6, 21.6, 22.4, 22.5, and 23.2 degrees 2.theta..
[0124] In embodiments, a crystalline form of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase has an XRPD pattern, when measured using Cu K
radiation, comprising diffraction angles of about 15.6, 16.5, 16.9,
18.7, 19.6, 21.6, and 22.5 degrees 2.theta..
[0125] In embodiments, a crystalline form of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase has an X-ray powder diffraction (XRPD)
pattern, when measured using Cu K radiation, comprising diffraction
angles of about 18.7, 19.6, 21.6, and 22.5 degrees 2.theta..
[0126] In one embodiment, the crystalline niraparib freebase is
characterised by XRPD diffraction angles having 2.theta. values
(and, optionally, relative intensity values) as recited in the
table below:
TABLE-US-00002 Pos. [.degree.2.theta.] Rel. Int. [%] 8.4 3 12.2 8
12.8 1 13.7 1 15.6 19 16.5 25 16.9 27 17.4 7 18.0 2 18.7 100 19.6
37 20.0 7 21.6 28 22.4 23 22.5 38 23.2 21 24.4 2 25.0 6 25.2 9 25.7
6 27.3 2 27.9 8 29.3 13 30.4 2 31.0 3 32.0 2 32.7 1 33.2 3 33.8 3
34.7 2
[0127] In one embodiment, the crystalline niraparib freebase is
characterised by an XRPD pattern substantially according to Table 1
of Example 1. In embodiments, the position of an XRPD diffraction
angle is within .+-.0.2000.degree. 2.theta. of the value specified
in Table 1; the d-spacing is within .+-.0.2000 .ANG. or .+-.0.1000
.ANG. of the value specified in Table 1; and/or the relative
intensity is within .+-.10% or .+-.5% of the value specified in
Table 1. In one embodiment, the crystalline niraparib freebase is
characterised by an XRPD pattern as shown (or substantially as
shown) in FIG. 1.
[0128] In embodiments, the crystalline niraparib freebase is
characterised by having an infra-red spectrum which includes a peak
at about 1652 cm.sup.-1 and a peak at about 1608 cm.sup.-1, e.g.
when measured using a FT-IR method as described herein. In
embodiments, the crystalline niraparib freebase is characterised by
infra-red peaks substantially according to Table 2 of Example 1. In
embodiments, an absorption peak is within .+-.1.00, 0.50, or 0.20
cm.sup.-1 of the value specified in Table 2. In embodiments, a
transmittance value is within .+-.10% or .+-.5% of the value
specified in Table 2. In embodiments, the crystalline niraparib
freebase is characterised by having an infra-red spectrum as shown
(or substantially as shown) in FIG. 4.
[0129] In embodiments, the crystalline niraparib freebase is
characterised by having a Raman spectrum which includes peaks at
shift values of about 960.3, about 1457.5 and about 1607.0
cm.sup.-1. In embodiments, the crystalline niraparib freebase is
characterised by Raman peaks substantially according to Table 3 of
Example 1. In embodiments, an absorption peak is within .+-.1.00,
0.50, or 0.20 cm.sup.-1 of the value specified in Table 3. In
embodiments, a transmittance value is within .+-.10% or .+-.5% of
the value specified in Table 3. In embodiments, the crystalline
niraparib freebase is characterised by having a Raman spectrum as
shown (or substantially as shown) in FIG. 5.
[0130] In embodiments, the crystalline niraparib freebase is
characterised by having a melting point in the range of about
185-195.degree. C., such as e.g. a melting point of about
190.degree. C.
[0131] The melting point may be determined, for example, by DTA
(e.g. as described in the following Examples). Thus, in
embodiments, the crystalline niraparib freebase is characterised by
a DTA thermogram in which the onset of melting (endothermic peak)
is about 188.0.degree. C. and/or wherein the peak minimum is about
191.8.degree. C. In embodiments, the crystalline niraparib freebase
is characterised by having a DTA thermogram as shown (or
substantially as shown) in FIG. 6 (lower trace).
[0132] The melting point may also be determined, for example, by
DSC (e.g. as described in the following Examples). Thus, in
embodiments, the crystalline niraparib freebase is characterised by
a DSC thermogram in which the onset of melting (endothermic peak)
is about 189.0.degree. C. and/or wherein the peak minimum is about
193.9.degree. C. In embodiments, the crystalline niraparib freebase
is characterised by a DSC thermogram as shown (or substantially as
shown) in FIG. 7.
[0133] In embodiments, the crystalline niraparib freebase is
characterised by not being hygroscopic. Hygroscopicity may be
determined, for example, by GVS (e.g. as described in the following
Examples). Thus, in embodiments, the crystalline niraparib freebase
is characterised by adsorbing less than about 1% by weight of water
up to about 90% relative humidity (e.g. at about 25.degree. C.). In
embodiments, the crystalline niraparib freebase is characterised by
adsorbing about 0.7% by weight of water up to about 90% relative
humidity (e.g. at about 25.degree. C.).
[0134] In embodiments, the crystalline niraparib freebase is
characterised by being stable under conditions of elevated humidity
and/or when in aqueous suspension.
[0135] In embodiments, substantially all (e.g. at least about 90%,
at least about 95%, at least about 99% or about 100%) of the
crystalline niraparib freebase retains the same form (e.g.
polymorphic form as assessed by XRPD) when exposed to about 90%
relative humidity at room temperature (e.g. at about 25.degree.
C.). In other embodiments, substantially all (e.g. at least about
90%, at least about 95%, at least about 99% or about 100%) of the
crystalline niraparib freebase retains the same form (e.g.
polymorphic form as assessed by XRPD) when exposed to about 90%
relative humidity at elevated temperature (e.g. at about 30.degree.
C., 40.degree. C., 50.degree. C., 60.degree. C. or 75.degree.
C.).
[0136] In embodiments, substantially all (e.g. at least about 90%,
at least about 95%, at least about 99% or about 100%) of the
crystalline niraparib freebase retains the same form (e.g.
polymorphic form as assessed by XRPD) when suspended in, or
slurried with, water. In other embodiments, substantially all (e.g.
at least about 90%, at least about 95%, at least about 99% or about
100%) of the crystalline niraparib freebase retains the same form
(e.g. polymorphic form as assessed by XRPD) when suspended in, or
slurried with, an aqueous buffer having a pH between about 1 and
about 7 (e.g. a buffer as in the present Examples).
[0137] In embodiments, the crystalline niraparib freebase is
characterised by being free of water or organic solvents, e.g. as
assessed by Karl Fisher analysis or gas chromatography.
[0138] In embodiments, the crystalline niraparib freebase is
substantially free of water, e.g. as assessed by Karl Fisher
analysis. In these embodiments, the water content is preferably
less than about 1%, such as e.g. less than about 0.9%, 0.8%, 0.7%,
0.6%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1%. The water content may be, for
example, between about 0.25% and about 0.35%, such as e.g. about
0.30%.
[0139] In embodiments, the crystalline niraparib freebase is
substantially free of organic solvents such as 2-MeTHF, e.g. as
assessed by GC. In these embodiments, the content of each (and
every) organic solvent is preferably less than about 1%, such as
e.g. less than about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or 0.05%. The
content of 2-MeTHF may be, for example, less than about 0.1%, such
as e.g. about 0.07%.
[0140] In a further aspect, the present disclosure provides a
crystalline Form II, III, IV, and/or V niraparib freebase. The
crystalline niraparib freebase may comprise Form II crystalline
niraparib freebase, e.g. as characterised herein. The crystalline
niraparib freebase may comprise Form III crystalline niraparib
freebase, e.g. as characterised herein. The crystalline niraparib
freebase may comprise Form IV crystalline niraparib freebase, e.g.
as characterised herein. The crystalline niraparib freebase may
comprise Form V crystalline niraparib freebase, e.g. as
characterised herein.
Form II Crystalline Niraparib Freebase
[0141] In one embodiment, the crystalline
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase comprises Form II crystalline niraparib
freebase, e.g. as characterised herein. Viewed from this aspect,
the invention provides a crystalline Form II of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase.
[0142] In embodiments, the crystalline Form II is characterised by
one or more (e.g. one, two, three, four or five) XRPD diffraction
angles at 2.theta. values of 17.3.degree., 21.7.degree.,
21.8.degree., 25.8.degree., and 21.6.degree.. In embodiments, the
crystalline Form II is characterised by one or more (e.g. one, two,
three, four or five) XRPD diffraction angles at 2.theta. values of
8.6.degree., 26.4.degree., 22.6.degree., 20.10, and 21.3.degree..
In embodiments, the crystalline Form II is characterised by XRPD
diffraction angles at 2.theta. values of 8.6.degree., 17.3.degree.,
20.10, 21.3.degree., 21.6.degree., 21.7.degree., 21.8.degree.,
22.6.degree., 25.8.degree. and 26.4.degree.. In embodiments, the
crystalline Form II is characterised by an XRPD diffraction angle
at a 2.theta. value of 3.2.degree..
[0143] In embodiments, the crystalline Form II is characterised by
XRPD diffraction angles having 2.theta. values (and, optionally,
relative intensity values) substantially as recited in Table 4 in
Example 3. In embodiments, the position of an XRPD diffraction
angle is within .+-.0.2000.degree. 2.theta. of the value specified
in Table 4; the d-spacing is within .+-.0.20000 .ANG. or
.+-.0.10000 .ANG. of the value specified in Table 4; and/or the
relative intensity is within .+-.10% or .+-.5% of the value
specified in Table 4. In embodiments, the crystalline Form II is
characterised by an XRPD pattern as shown (or substantially as
shown) in FIG. 10.
Form III Crystalline Niraparib Freebase
[0144] In one embodiment, the crystalline
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase comprises Form III crystalline niraparib
freebase, e.g. as characterised herein. Viewed from this aspect,
the invention provides a crystalline Form III of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase.
[0145] In embodiments, the crystalline Form III is characterised by
one or more (e.g. one, two, three, four or five) XRPD diffraction
angles at 2.theta. values of 17.3.degree., 20.5.degree.,
13.6.degree., 21.3.degree. and 21.7.degree.. In embodiments, the
crystalline Form III is characterised by one or more (e.g. one,
two, three, four or five) XRPD diffraction angles at 2.theta.
values of 22.3.degree., 13.8.degree., 24.10, 23.7.degree. and
14.6.degree.. In embodiments, the crystalline Form III is
characterised by XRPD diffraction angles at 2.theta. values of
13.6.degree., 13.8.degree., 14.6.degree., 17.3.degree.,
20.5.degree., 21.3.degree., 21.7.degree., 22.3.degree.,
23.7.degree. and 24.1.degree.. In embodiments, the crystalline Form
III is characterised by an XRPD diffraction angle at a 2.theta.
value of 20.5.degree.. In embodiments, the crystalline Form III is
characterised by XRPD diffraction angles at 2.theta. values of
20.5.degree. and 23.7.degree.. In embodiments, the crystalline Form
III is characterised by XRPD diffraction angles at 2.theta. values
of 20.5.degree., 23.7.degree. and 10.1.degree..
[0146] In embodiments, the crystalline Form III is characterised by
XRPD diffraction angles having 2.theta. values (and, optionally,
relative intensity values) substantially as recited in Table 5 in
Example 3. In embodiments, the position of an XRPD diffraction
angle is within .+-.0.2000.degree. 2.theta. of the value specified
in Table 5; the d-spacing is within .+-.0.20000 .ANG. or
.+-.0.10000 .ANG. of the value specified in Table 5; and/or the
relative intensity is within .+-.10% or .+-.5% of the value
specified in Table 5. In embodiments, the crystalline Form III is
characterised by an XRPD pattern as shown (or substantially as
shown) in FIG. 11.
Form IV Crystalline Niraparib Freebase
[0147] In one embodiment, the crystalline
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase comprises Form IV crystalline niraparib
freebase, e.g. as characterised herein. Viewed from this aspect,
the invention provides a crystalline Form IV of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase.
[0148] In embodiments, the crystalline Form IV is characterised by
one or more (e.g. one, two, three, four or five) XRPD diffraction
angles at 2.theta. values of 21.9.degree., 20.1.degree.,
18.9.degree., 22.1.degree. and 19.7.degree.. In embodiments, the
crystalline Form IV is characterised by one or more (e.g. one, two,
three, four or five) XRPD diffraction angles at 2.theta. values of
14.4.degree., 17.3.degree., 17.10, 19.8.degree. and 17.6.degree..
In embodiments, the crystalline Form IV is characterised by XRPD
diffraction angles at 2.theta. values of 14.4.degree., 17.10,
17.3.degree., 17.6.degree., 18.9.degree., 19.7.degree.,
19.8.degree., 20.10, 21.9.degree. and 22.1.degree.. In embodiments,
the crystalline Form IV is characterised by an XRPD diffraction
angle at a 2.theta. value of 27.6.degree.. In embodiments, the
crystalline Form IV is characterised by XRPD diffraction angles at
2.theta. values of 27.6.degree. and 24.8.degree.. In embodiments,
the crystalline Form IV is characterised by XRPD diffraction angles
at 2.theta. values of 27.6.degree., 24.8.degree. and
7.3.degree..
[0149] In embodiments, the crystalline Form IV is characterised by
XRPD diffraction angles having 2.theta. values (and, optionally,
relative intensity values) substantially as recited in Table 6 in
Example 4. In embodiments, the position of an XRPD diffraction
angle is within .+-.0.2000.degree. 2.theta. of the value specified
in Table 6; the d-spacing is within .+-.0.20000 .ANG. or
.+-.0.10000 .ANG. of the value specified in Table 6; and/or the
relative intensity is within .+-.10% or .+-.5% of the value
specified in Table 6. In embodiments, the crystalline Form IV is
characterised by an XRPD pattern as shown (or substantially as
shown) in FIG. 14 (the 122.degree. C. trace).
Form V Crystalline Niraparib Freebase
[0150] In one embodiment, the crystalline
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase comprises Form V crystalline niraparib
freebase, e.g. as characterised herein. Viewed from this aspect,
the invention provides a crystalline Form V of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase.
[0151] In embodiments, the crystalline Form V is characterised by
one or more (e.g. one, two, three, four or five) XRPD diffraction
angles at 2.theta. values of 20.8.degree., 21.6.degree.,
5.9.degree., 21.3.degree. and 14.4.degree.. In embodiments, the
crystalline Form V is characterised by one or more (e.g. one, two,
three, four or five) XRPD diffraction angles at 2.theta. values of
14.8.degree., 16.7.degree., 15.8.degree., 19.5.degree. and
29.2.degree.. In embodiments, the crystalline Form V is
characterised by XRPD diffraction angles at 2.theta. values of
5.9.degree., 14.4.degree., 14.8.degree., 15.8.degree.,
16.7.degree., 19.5.degree., 20.8.degree., 21.3.degree.,
21.6.degree. and 29.2.degree.. In embodiments, the crystalline Form
V is characterised by an XRPD diffraction angle at a 2.theta. value
of 5.9.degree.. In embodiments, the crystalline Form V is
characterised by an XRPD diffraction angle at a 2.theta. value of
5.9.degree. and further characterised by XRPD diffraction angles at
2.theta. values of 15.10 and/or 9.7.degree.. In embodiments, the
crystalline Form V is characterised by XRPD diffraction angles at
2.theta. values of 5.9.degree., 15.1.degree., 9.7.degree. and
8.0.degree..
[0152] In embodiments, the crystalline Form V is characterised by
XRPD diffraction angles having 2.theta. values (and, optionally,
relative intensity values) substantially as recited in Table 8 in
Example 5. In embodiments, the position of an XRPD diffraction
angle is within .+-.0.2000.degree. 2.theta. of the value specified
in Table 8; the d-spacing is within .+-.0.20000 .ANG. or
.+-.0.10000 .ANG. of the value specified in Table 8; and/or the
relative intensity is within .+-.10% or .+-.5% of the value
specified in Table 8. In embodiments, the crystalline Form V is
characterised by an XRPD pattern as shown (or substantially as
shown) in FIG. 15.
Compositions
[0153] The present disclosure provides a composition (e.g. a
pharmaceutical composition) comprising crystalline
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase. In embodiments, the composition is
substantially free of amorphous niraparib. In embodiments, the
composition is substantially free of a (e.g. any) pharmaceutically
acceptable salt of niraparib. In embodiments, the composition is
substantially free of any other solid form of niraparib freebase or
niraparib salt (besides a crystalline niraparib freebase as
described herein). In embodiments, less than about 10% (e.g. less
than about 5%, less than about 4%, less than about 3%, less than
about 2% or less than about 1%) of the total niraparib in the
composition is in the form of said amorphous niraparib, said
pharmaceutically acceptable salt of niraparib, and/or said other
solid form of niraparib freebase or niraparib salt.
[0154] The present disclosure provides a pharmaceutical composition
comprising crystalline niraparib freebase as described herein and
at least one pharmaceutically acceptable excipient. The
pharmaceutical compositions may be used according to the methods
disclosed herein.
[0155] In one embodiment, the pharmaceutical composition comprises
crystalline niraparib freebase Form I as described herein. In
embodiments, the pharmaceutical composition is substantially free
from (e.g. as assessed by XRPD) Form II, Form III, Form IV and/or
Form V crystalline niraparib freebase. In embodiments, the
pharmaceutical composition is substantially free from (e.g. as
assessed by XRPD) Form II, Form III, Form IV and Form V crystalline
niraparib freebase. In embodiments, the pharmaceutical composition
is substantially free from (e.g. as assessed by XRPD) amorphous
niraparib freebase.
[0156] In embodiments, the pharmaceutical composition comprises
about 20-80 wt % of crystalline niraparib freebase, such as e.g.
about 45-70 wt %, about 40-50 wt %, about 45-55 wt %, about 50-60
wt %, about 55-65 wt %, about 60-70 wt %, about 65-75 wt %, about
70-80 wt %, or about 40-60 wt % of crystalline niraparib
freebase.
[0157] The pharmaceutically acceptable excipient can be any such
excipient known in the art including those described in, for
example, Remington's Pharmaceutical Sciences, Mack Publishing Co.
(A. R. Gennaro edit. 1985). Pharmaceutical compositions of the
compounds presently disclosed may be prepared by conventional means
known in the art including, for example, mixing at least one
presently disclosed compound with a pharmaceutically acceptable
excipient.
[0158] Exemplary pharmaceutically acceptable excipients for the
purposes of pharmaceutical compositions disclosed herein include,
but are not limited to, binders, disintegrants, superdisintegrants,
lubricants, diluents, fillers, flavors, glidants, sorbents,
solubilizers, chelating agents, emulsifiers, thickening agents,
dispersants, stabilizers, suspending agents, adsorbents,
granulating agents, preservatives, buffers, coloring agents and
sweeteners or combinations thereof. In embodiments, the
pharmaceutically acceptable excipient comprises hydroxypropyl
methylcellulose, e.g. low substituted hydroxypropyl cellulose. In
embodiments, the pharmaceutically acceptable excipient comprises
lactose, e.g. lactose monohydrate. In embodiments, the
pharmaceutically acceptable excipient comprises magnesium stearate.
In some embodiments, the pharmaceutically acceptable excipient is
lactose monohydrate and magnesium stearate.
[0159] Various useful fillers or diluents include, but are not
limited to, calcium carbonate (Barcroft.TM., MagGran.TM.,
Millicarb.TM., Pharma-Carb.TM., Precarb.TM., Sturcal.TM., Vivapres
Ca.TM.), calcium phosphate, dibasic anhydrous (Emcompress
Anhydrous.TM., Fujicalin.TM.) calcium phosphate, dibasic dihydrate
(Calstar.TM., Di-Cafos.TM., Emcompress.TM.), calcium phosphate
tribasic (Tri-Cafos.TM., TRI-TAB.TM.), calcium sulphate
(Destab.TM., Drierite.TM., Snow White.TM., Cal-Tab.TM.,
Compactrol.TM.), cellulose powdered (Arbocel.TM., Elcema.TM.,
Sanacet.TM.), silicified microcrystailine cellulose, cellulose
acetate, compressible sugar (Di-Pac.TM.), confectioner's sugar,
dextrates (Candex.TM., Emdex.TM.), dextrin (Avedex.TM.,
Caloreen.TM., Primogran W.TM.), dextrose (Caridex.TM.,
Dextrofin.TM., Tab fine D-IOO.TM.) fructose (Fructofin.TM.,
Krystar.TM.), kaolin (Lion.TM., Sim 90.TM.), lactitol (Finlac
DC.TM., Finlac MCX.TM.), lactose (Anhydrox.TM., CapsuLac.TM.,
Fast-Flo.TM., FlowLac.TM., GranuLac.TM., InhaLac.TM.,
Lactochem.TM., Lactohaie.TM., Lactopress.TM., Microfme.TM.,
Microtose.TM., Pharmatose.TM., Prisma Lac.TM., Respitose.TM.,
SacheLac.TM., SorboLac.TM., Super-Tab.TM., Tablettose.TM.,
Wyndale.TM., Zeparox.TM.), lactose monohydrate, magnesium
carbonate, magnesium oxide (MagGran MO.TM.), maltodextrin (C*Dry
MD.TM., Lycatab DSH.TM., Maldex.TM., Maitagran.TM., Maltrin.TM.,
Maltrin QD.TM., Paselli MD 10 PH.TM., Star-Dri.TM.) maltose
(Advantose 100.TM.), mannitol (Mannogem.TM., Pearlitol.TM.),
microcrystalline cellulose (Avicel PH.TM., Celex.TM., Celphere.TM.,
Ceolus KG.TM., Emcocel.TM., Pharmacel.TM., Tabulose.TM.
Vivapur.TM.), polydextrose (Litesse.TM.), simethicone (Dow Corning
Q7-2243 LVA.TM., Cow Coming Q7-2587.TM., Sentry Simethicone.TM.),
sodium alginate (Keltone.TM., Protanal.TM.) sodium chloride
(Alberger.TM.), sorbitol (Liponec 70-NC.TM., Liponic 76-NCv,
Meritol.TM., Neosorb.TM., Sorbitol Instant.TM., Sorbogem.TM.),
starch (Flufiex W.TM., Instant Pure-Cote.TM., Melojei.TM., Meritena
Paygel 55.TM., Perfectamyl D6PH.TM., Pure-Cote.TM., Pure-Dent.TM.,
Pure-Gel.TM., Pure-Set.TM., Purity 21.TM., Purity 826.TM., Tablet
White.TM.), pregelatinized starch, sucrose, trehalose and xylitol,
or mixtures thereof. In embodiments, the filler comprises lactose
monohydrate.
[0160] In embodiments, the composition comprises about 5-90% by
weight of filler, e.g. the filler is present in an amount of about
10-80%, about 15-70%, about 20-60% or about 25-50% by weight. For
example, the composition may comprise about 40%, 45%, 50%, 55%,
60%, 65%, 70%, 75% or 80% by weight of filler. In embodiments, the
composition comprises from about 25 mg to about 1000 mg of filler,
e.g. the filler is present in an amount of from about 50 mg to
about 750 mg, from about 100 mg to about 600 mg, from about 150 mg
to about 500 mg or from about 200 mg to about 450 mg. For example,
the composition may comprise about 250, 275, 300, 325, 350, 375,
400, 425, 450, 475 or 500 mg of filler.
[0161] Various useful lubricants include, but are not limited to,
calcium stearate (HyQual.TM.), glycerine monostearate (Imwitor.TM.
191 and 900, Kessco GMS5.TM., 450 and 600, Myvaplex 600P.TM.,
Myvatex.TM., Rita GMS.TM., Stepan GMS.TM., Tegin.TM., Tegin.TM. 503
and 515, Tegin 4100.TM., Tegin M.TM., Unimate GMS.TM.), glyceryl
behenate (Compritol 888 ATO.TM.), glyceryl palmitostearate
(Precirol ATO 5.TM.), hydrogenated castor oil (Castorwax MP 80.TM.,
Croduret.TM., Cutina HR.TM., Fancol.TM., Simulsol 1293.TM.),
hydrogenated vegetable oil 0 type I (Sterotex.TM., Dynasan P60.TM.,
Hydrocote.TM., Lipovol HS-K.TM., Sterotex HM.TM.) magnesium lauryl
sulphate, magnesium stearate, medium-chain triglycerides (Captex
300.TM., Labrafac CC.TM., Miglyol 810.TM., Neobee MS.TM.,
Nesatol.TM., Waglinol 3/9280.TM.), poloxamer (Pluronic.TM.,
Synperonic.TM.), polyethylene 5 glycol (Carbowax Sentry.TM.,
Lipo.TM., Lipoxol.TM., Lutrol E.TM., Pluriol E.TM.), sodium
benzoate (Antimol.TM.), sodium chloride, sodium lauryl sulphate
(Elfan 240.TM., Texapon Kl 2P.TM.), sodium stearyl fumarate
(Pruv.TM.), stearic acid (Hystrene.TM., Industrene.TM., Kortacid
1895.TM., Pristerene.TM.), talc (Altaic.TM., Luzenac.TM., Luzenac
Pharma.TM., Magsil Osmanthus.TM., 0 Magsil Star.TM.,
Superiore.TM.), sucrose stearate (Surfhope SE Pharma D-1803 F.TM.)
and zinc stearate (HyQual.TM.) or mixtures thereof. Examples of
suitable lubricants include, but are not limited to, magnesium
stearate, calcium stearate, zinc stearate, stearic acid, talc,
glyceryl behenate, polyethylene glycol, polyethylene oxide
polymers, sodium lauryl sulfate, magnesium lauryl sulfate, sodium
oleate, sodium stearyl fumarate, DL-leucine, colloidal silica. In
embodiments, the lubricant comprises magnesium stearate.
[0162] In embodiments, the composition comprises about 0.1-5% by
weight of lubricant, e.g. the lubricant is present in an amount of
about 0.2-2%, about 0.3-1%, about 0.4-0.75% or about 0.5-0.7% by
weight. For example, the composition may comprise about 0.3%, 0.4%,
0.5%, 0.6%, 0.7% or 0.8% by weight of lubricant. In embodiments,
the composition comprises from about 0.01 mg to about 10 mg of
lubricant, e.g. the lubricant is present in an amount of from about
0.01 mg to 0.05 mg, 0.05 mg to 0.1 mg, 0.1 mg to 0.2 mg, 0.2 mg to
0.25 mg, 0.25 mg to 0.5 mg, 0.5 mg to 0.75 mg, 0.7 mg to 0.95 mg,
0.9 mg to 1.15 mg, 1.1 mg to 1.35 mg, 1.3 mg to 1.5 mg, 1.5 mg to
1.75 mg, 1.75 to 1.95 mg, 1.9 mg to 2.15 mg, 2.1 mg to 2.35 mg, 2.3
mg to 2.55 mg, 2.5 mg to 2.75 mg, 2.7 mg to 3.0 mg, 2.9 mg to 3.15
mg, 3.1 mg to 3.35 mg, 3.3 mg to 3.5 mg, 3.5 mg to 3.75 mg, 3.7 mg
to 4.0 mg, 4.0 mg to 4.5 mg, 4.5 mg to 5.0 mg, 5.0 mg to 5.5 mg,
5.5 mg to 6.0 mg, 6.0 mg to 6.5 mg, 6.5 mg to 7.0 mg, 7.0 mg to 7.5
mg, 7.5 mg to 8.0 mg, 8.0 mg to 8.5 mg, 8.5 mg to 9.0 mg, 9.0 mg to
9.5 mg, or 9.5 mg to 10.0 mg. For example, the composition may
comprise about 0.01 mg, 0.05 mg, 0.1 mg, 0.2 mg, 0.25 mg, 0.5 mg,
0.7 mg, 0.9 mg, 1.1 mg, 1.3 mg, 1.5 mg, 1.7 mg, 1.9 mg, 2. mg, 2.3
mg, 2.5 mg, 2.75 mg, 3.0 mg, 3.1 mg, 3.3 mg, 3.5 mg, 3.7 mg, 4.0
mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg,
8.5 mg, 9.0 mg, 9.5 mg or 10.0 mg by weight of lubricant.
[0163] Various useful disintegrants include, but are not limited
to, alginic acid (Protacid.TM., Satialgine H8.TM.), calcium
phosphate, tribasic (TRI-TAB.TM.) carboxymethylcellulose calcium
(ECG 505.TM.), carboxymethylcellulose sodium (Akucell.TM.,
Finnfix.TM., Nymcel Tylose CB.TM.), colloidal silicon dioxide
(Aerosil.TM., Cab-O-Sil.TM., Wacker HDK.TM.), croscarmellose sodium
(Ac-Di-Sol.TM., Pharmacel XL.TM., Primellose.TM., Solutab.TM.,
Vivasol.TM.), crospovidone (Collison CL.TM., Collison CL-M.TM.,
Polyplasdone XL.TM.), docusate sodium, guar gum (Meyprodor.TM.,
Meyprofm.TM., Meyproguar.TM.), low substituted hydroxypropyl
cellulose, magnesium aluminum silicate (Magnabite.TM.,
Neusilin.TM., Pharmsorb.TM., Veegum.TM.), methylcellulose
(Methocel.TM., Metolose.TM.), microcrystalline cellulose (Avicel
PH.TM., Ceoius KG.TM., Emcoel.TM., Ethispheres.TM., Fibrocel.TM.,
Pharmacel.TM., Vivapur.TM.), povidone (Collison.TM., Plasdone.TM.)
sodium alginate (Kelcosol.TM., Ketone.TM., Protanal.TM.), sodium
starch glycolate, polacrilin potassium (Amberlite IRP88.TM.),
silicified microcrystalline cellulose (ProSotv.TM.), starch (Aytex
P.TM., Fluftex W.TM., Melojel.TM., Meritena.TM., Paygel 55.TM.,
Perfectamyl D6PH.TM., Pure-Bind.TM., Pure-Cote.TM., Pure-Dent.TM.,
Purity 21.TM., Purity 826.TM., Tablet White.TM.) or pre-gelatinized
starch (Lycatab PGS.TM., Merigel.TM., National 78-1551.TM.,
Pharma-Gel.TM., Prejel.TM., Sepistab ST 200.TM., Spress B820.TM.,
Starch 1500 G.TM., Tablitz.TM., Unipure LD.TM.), or mixtures
thereof. In embodiments, the composition comprises about 0 to about
10% by weight of disintegrant.
[0164] Various useful glidants include, but are not limited to,
tribasic calcium phosphate (TRI-TAB.TM.), calcium silicate,
cellulose powdered (Sanacel.TM., Solka-Floe.TM.), colloidal silicon
dioxide (Aerosil.TM., Cab-O-Sil M-5P.TM., Wacker HDK.TM.),
magnesium silicate, magnesium trisilicate, starch (Melojel.TM.,
Meritena.TM., Paygel 55.TM., Perfectamyl D6PH.TM., Pure-Bind.TM.,
Pure-Cote.TM., Pure-Dent.TM., Pure-Gel.TM., Pure-Set.TM., Purity
21.TM., Purity 826.TM., Tablet White.TM.) and talc (Luzenac
Pharma.TM., Magsil Osmanthus.TM., Magsil Star.TM., Superiore.TM.),
or mixtures thereof. In embodiments, the composition comprises
about 0 to about 15% by weight of glidant.
[0165] Pharmaceutically acceptable surfactants include, but are
limited to, both non-ionic and ionic surfactants suitable for use
in pharmaceutical dosage forms. Ionic surfactants may include one
or more of anionic, cationic or zwitterionic surfactants. Various
useful surfactants include, but are not limited to, sodium lauryl
sulfate, monooleate, monolaurate, monopalmitate, monostearate or
another ester of olyoxyethylene sorbitane, sodium
dioctylsulfosuccinate, lecithin, stearyic alcohol, cetostearylic
alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene
fatty acid glycerides, poloxamer, or any other commercially
available co-processed surfactant like SEPITRAP.RTM. 80 or
SEPITRAP.RTM. 4000 and mixtures thereof. In embodiments, the
composition comprises about 0 to about 5% by weight of
surfactant.
[0166] In embodiments, a solid pharmaceutical composition of the
disclosure comprises crystalline niraparib freebase as described
herein, a diluent and a lubricant. In embodiments, the solid
pharmaceutical composition comprises crystalline niraparib freebase
as described herein (e.g. crystalline niraparib freebase Form I),
lactose monohydrate and magnesium stearate.
[0167] In embodiments, a solid pharmaceutical composition of the
disclosure comprises (by weight of the composition) about 20-60%
crystalline niraparib freebase, about 20-80% diluent and about
0.1-5% lubricant. In embodiments, the pharmaceutical composition
comprises (by weight of the composition) about 40-60% crystalline
niraparib freebase, about 40-70% diluent (e.g. lactose monohydrate)
and about 0.2-2% lubricant (e.g. magnesium stearate).
[0168] The pharmaceutical compositions can be formulated so as to
provide slow, extended, or controlled release of the active
ingredient therein using, for example, hydroxypropylmethyl
cellulose in varying proportions to provide the desired release
profile, other polymer matrices, liposomes and/or microspheres. The
pharmaceutical compositions can also optionally contain opacifying
agents and may be of a composition that releases the active
ingredient(s) only, or preferentially, in a certain portion of the
gastrointestinal tract, optionally, in a delayed manner, e.g. by
using an enteric coating. Examples of embedding compositions
include polymeric substances and waxes. The active ingredient can
also be in micro-encapsulated form, if appropriate, with one or
more pharmaceutically acceptable carriers, excipients, or diluents
well known in the art (see, e.g. Remington's). The compounds
presently disclosed may be formulated for sustained delivery
according to methods well known to those of ordinary skill in the
art. Examples of such formulations can be found in U.S. Pat. Nos.
3,119,742; 3,492,397; 3,538,214; 4,060,598; and 4,173,626.
Synthesis
[0169] Crystalline niraparib freebase may be prepared from
amorphous niraparib freebase, e.g. by
dissolution/recrystallisation, by slurrying with solvent such as
water, or by heating/cooling. It may also be prepared from a
niraparib acid addition salt (such as e.g. niraparib tosylate
monohydrate) by conversion with a base such as dilute NaOH. Methods
for the preparation of crystalline niraparib freebase are
illustrated in the following Examples.
[0170] In particular, crystalline niraparib freebase may be
prepared by recrystallization from, or by slurrying with, an
organic solvent, such as e.g. 2-MeTHF.
[0171] Alternative methods for the preparation of crystalline
niraparib freebase would be apparent to the skilled person on the
basis of their common general knowledge and the teaching of the
present application.
Medical Indications
[0172] The crystalline
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase and pharmaceutical compositions described
herein are useful in therapy, in particular in the therapeutic
treatment of PARP-1 and PARP-2 mediated conditions in a subject.
Methods for treating PARP-1 and PARP-2 mediated conditions are
described in WO 2018/005818.
[0173] In certain embodiments, crystalline niraparib freebase may
provide improved therapeutic benefits as compared to administration
of a different form of niraparib (e.g. a crystalline niraparib
tosylate monohydrate). In embodiments, an improved therapeutic
benefit may be a change (e.g. a reduction) in the incidence and/or
severity of an unwanted side-effect observed with a different form
of niraparib. In embodiments, an unwanted side effect is
thrombocytopenia, anemia, neutropenia, leukopenia, palpitations,
nausea, constipation, vomiting, abdominal pain/distention,
mucositis/stomatitis, diarrhea, dyspepsia, dry mouth,
fatigue/asthenia, decreased appetite, urinary tract infection,
AST/ALT elevation, myalgia, back pain, arthralgia, headache,
dizziness, dysgeusia, insomnia, anxiety, nasopharyngitis, dyspnea,
cough, rash, or hypertension. In embodiments, an unwanted
side-effect is a hematological side-effect (e.g. thrombocytopenia,
anemia, neutropenia, or leukopenia). In embodiments, an unwanted
side-effect is a non-hematological side effect. In embodiments, an
unwanted side-effect is a cardiovascular effect (e.g.
palpitations). In embodiments, an unwanted side-effect is a
gastrointestinal disorder (e.g. nausea, constipation, vomiting,
abdominal pain/distension, mucositis/stomatitis, diarrhea,
dyspepsia, or dry mouth). In embodiments, an unwanted side-effect
is fatigue or asthenia. In embodiments, an unwanted side-effect is
a metabolism or nutrition disorder (e.g. decreased appetite). In
embodiments, an unwanted side-effect is an infection or infestation
(e.g. urinary tract infection). In embodiments, an unwanted
side-effect is elevation in AST/ALT. In embodiments, an unwanted
side-effect is a musculoskeletal or connective tissue disorder
(e.g. myalgia, back pain, or arthralgia). In embodiments, an
unwanted side-effect is a nervous system disorder (e.g. headache,
dizziness, or dysgeusia). In embodiments, an unwanted side-effect
is a psychiatric disorder (e.g. insomnia or anxiety). In
embodiments, an unwanted side-effect is a respiratory, thoracic, or
mediastinal disorder (e.g. nasopharyngitis, dyspnea, or cough). In
embodiments, an unwanted side-effect is a skin or subcutaneous
tissue disorder (e.g. rash). In embodiments, an unwanted
side-effect is a vascular disorder (e.g. hypertension).
[0174] In embodiments, an unwanted side-effect is myelodysplastic
syndrome/acute myeloid leukemia. In embodiments, an unwanted
side-effect is bone marrow suppression.
[0175] Subjects to be treated according to the methods described
herein include vertebrates, such as mammals. In preferred
embodiments the mammal is a human patient.
[0176] In one aspect, the present disclosure provides crystalline
niraparib freebase as described herein, e.g. crystalline niraparib
freebase Form I, for use in therapy. Also provided is the use of
crystalline niraparib freebase as described herein, e.g.
crystalline niraparib freebase Form I, in the manufacture of a
medicament.
[0177] In another aspect, the present disclosure provides a method
of treating cancer, stroke, autoimmune diabetes, a neurological
disease, an inflammatory disease, a metabolic disease or a
cardiovascular disease in a subject, the method comprising
administering to the subject an effective amount of niraparib
freebase as described herein, e.g. crystalline niraparib freebase
Form I. Also provided is crystalline niraparib freebase as
described herein, e.g. crystalline niraparib freebase Form I, for
use in a method of treating cancer, stroke, autoimmune diabetes, a
neurological disease, an inflammatory disease, a metabolic disease
or a cardiovascular disease. Further provided is the use of
crystalline niraparib freebase as described herein, e.g.
crystalline niraparib freebase Form I, in the manufacture of a
medicament for use in a method of treating cancer, stroke,
autoimmune diabetes, a neurological disease, an inflammatory
disease, a metabolic disease or a cardiovascular disease.
[0178] In a further aspect, the disclosure provides a method of
treating a PARP-1 and/or PARP-2 mediated condition in a subject,
the method administering to the subject an effective amount of
niraparib freebase as described herein, e.g. crystalline niraparib
freebase Form I. Also provided is crystalline niraparib freebase as
described herein, e.g. crystalline niraparib freebase Form I, for
use in a method of treating a PARP-1 and/or PARP-2 mediated
condition. Further provided is the use of crystalline niraparib
freebase as described herein, e.g. crystalline niraparib freebase
Form I, in the manufacture of a medicament for use in a method of
treating a PARP-1 and/or PARP-2 mediated condition.
Oncological Conditions (Cancers)
[0179] PARP inhibitors have shown activity as a monotherapy against
tumors with existing DNA repair defects, such as BRCA1 and BRCA2,
and as a combination therapy when administered together with
anti-cancer agents that induce DNA damage. Despite several advances
in treatment of ovarian cancer, most patients eventually relapse,
and subsequent responses to additional treatment are often limited
in duration. Women with germline BRCA1 or BRCA2 mutations have an
increased risk for developing high grade serous ovarian cancer
(HGSOC), and their tumors appear to be particularly sensitive to
treatment with a PARP inhibitor. In addition, published scientific
literature indicates that patients with platinum sensitive HGSOC
who do not have germline BRCA1 or BRCA2 mutations may also
experience clinical benefit from treatment with a PARP inhibitor.
Since PARP inhibitors block DNA repair, in the context of cancer
cells with the BRCA mutation, PARP inhibition results in synthetic
lethality. For this reason, patients with germline mutations in a
BRCA gene show marked clinical benefit following treatment with a
PARP inhibitor.
[0180] In one embodiment, the condition to be treated is a cancer,
especially a cancer which is associated with DNA repair defects,
such as BRCA1 and/or BRCA2 mutations.
[0181] In embodiments, the cancer is a recurrent cancer.
[0182] In embodiments, a cancer is breast cancer, ovarian cancer,
cervical cancer, epithelial ovarian cancer, fallopian tube cancer,
primary peritoneal cancer, endometrial cancer, prostate cancer,
testicular cancer, pancreatic cancer, esophageal cancer, head and
neck cancer, gastric cancer, bladder cancer, lung cancer (e.g.
adenocarcinoma, NSCLC and SCLC), bone cancer (e.g. osteosarcoma),
colon cancer, rectal cancer, thyroid cancer, brain and central
nervous system cancers, glioblastoma, neuroblastoma, neuroendocrine
cancer, rhabdoid cancer, keratoacanthoma, epidermoid carcinoma,
seminoma, melanoma, sarcoma (e.g. liposarcoma), bladder cancer,
liver cancer (e.g. hepatocellular carcinoma), kidney cancer (e.g.
renal cell carcinoma), myeloid disorders (e.g. AML, CML,
myelodysplastic syndrome and promyelocytic leukemia), and lymphoid
disorders (e.g. leukemia, multiple myeloma, mantle cell lymphoma,
ALL, CLL, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma,
non-Hodgkin's lymphoma, hairy cell lymphoma) may be treated with
compounds and methods described herein.
[0183] The cancer may be selected from head and neck cancer, breast
cancer (e.g. metastatic breast cancer), prostate cancer (e.g.
metastatic prostate cancer), testicular cancer, ovarian cancer,
endometrial cancer, colon cancer, rectal cancer, lung cancer (e.g.
non-small cell lung cancer), bladder cancer, pancreatic cancer
(e.g. metastatic pancreatic cancer), brain and central nervous
system cancers (e.g. primary malignant brain tumour),
neuroendocrine cancer, rhabdoid cancer, gynaecological cancer,
peritoneal cancer, skin cancer, thyroid cancer, oesophageal cancer,
cervical cancer, gastric cancer, liver cancer, stomach cancer,
renal cell cancer, biliary tract cancer, hematologic cancer, bone
cancer, and blood cancer.
[0184] In embodiments, the cancer is selected from colorectal
carcinoma, large intestinal colon carcinoma, head and neck
carcinoma, seminoma, sarcoma, lung carcinoma, lung adenocarcinoma,
bladder carcinoma, Barret's adenocarcinoma, renal carcinoma,
epidermoid carcinoma, and hepatocarcinoma. In embodiments, the
cancer is selected from glioblastoma, astrocytoma, melanoma (e.g.
metastatic melanoma), mesothelioma, myeloma, keratoacanthoma,
neuroblastoma, histiocytic lymphoma, and lymphocytic leukaemia. In
embodiments, the cancer is a solid tumour (e.g. a malignant solid
tumour) which may be an advanced-stage solid tumour.
[0185] In embodiments, the cancer is a gynaecological cancer, e.g.
selected from ovarian cancer, cancer of the fallopian tube(s),
peritoneal cancer and breast cancer. In some embodiments, the
gynaecological cancer is associated with HRD and/or BRCA1/2
mutation(s). In some embodiments, the gynaecological cancer is
platinum sensitive. In other embodiments, the gynaecological cancer
is not platinum sensitive. In embodiments, the gynaecological
cancer previously responded (e.g. partially or fully) to
platinum-based therapy but has since developed resistance to
platinum-based therapy.
[0186] In embodiments, the cancer is ovarian cancer, cancer of the
fallopian tube(s), or peritoneal cancer (e.g. primary peritoneal
cancer). In other embodiments, the cancer is breast cancer.
[0187] In some embodiments, the methods of the invention treat
subjects with ovarian cancer. In some embodiments, the methods of
the invention treat subjects with epithelial ovarian cancer. In
some embodiments, the methods of the invention treat subjects with
fallopian tube cancer. In some embodiments, the methods of the
invention treat subjects with primary peritoneal cancer. In some
embodiments, the methods of the invention treat subjects with
recurrent ovarian cancer. In some embodiments, the methods of the
invention treat subjects with recurrent epithelial ovarian cancer.
In some embodiments, the methods of the invention treat subjects
with recurrent fallopian tube cancer. In some embodiments, the
methods of the invention treat subjects with recurrent primary
peritoneal cancer.
[0188] In some embodiments, the methods of the invention treat
subjects with recurrent ovarian cancer following a complete or
partial response to a chemotherapy, such as a platinum-based
chemotherapy. In some embodiments, the methods of the invention
treat subjects with recurrent epithelial ovarian cancer following a
complete or partial response to a chemotherapy, such as a
platinum-based chemotherapy. In some embodiments, the methods of
the invention treat subjects with recurrent fallopian tube cancer
following a complete or partial response to a chemotherapy, such as
a platinum-based chemotherapy. In some embodiments, the methods of
the invention treat subjects with recurrent primary peritoneal
cancer following a complete or partial response to a chemotherapy,
such as a platinum-based chemotherapy.
[0189] In some embodiments, the methods of the invention treat
subjects with recurrent ovarian cancer, recurrent epithelial
ovarian cancer, recurrent fallopian tube cancer and/or recurrent
primary peritoneal cancer following a complete or partial response
to a platinum-based chemotherapy, wherein the subjects begin the
treatment no later than 8 weeks after their most recent
platinum-containing regimen. For example, subjects can begin
treatment with niraparib about 7 weeks after their most recent
platinum-containing regimen. For example, subjects can begin
treatment with niraparib about 6 weeks after their most recent
platinum-containing regimen. For example, subjects can begin
treatment with niraparib about 6 weeks after their most recent
platinum-containing regimen. For example, subjects can begin
treatment with niraparib about 5 weeks after their most recent
platinum-containing regimen. For example, subjects can begin
treatment with niraparib about 4 weeks after their most recent
platinum-containing regimen. For example, subjects can begin
treatment with niraparib about 3 weeks after their most recent
platinum-containing regimen. For example, subjects can begin
treatment with niraparib about 2 weeks after their most recent
platinum-containing regimen. For example, subjects can begin
treatment with niraparib about 1 week after their most recent
platinum-containing regimen.
[0190] In embodiments, the method treats cancer in a subject
exhibiting a positive HRD status. In some embodiments, the subject
is further characterized by the absence of a mutation in BRCA1
and/or BRCA2. A positive HRD status may be determined by
quantifying in a patient sample a number of Indicator Chromosomal
Aberration regions. In some embodiments, a tumor sample from the
subject has a positive HRD status.
[0191] In other embodiments, the method treats cancer in a subject
exhibiting an absence of HRD, e.g. a subject having
platinum-sensitive recurrent ovarian cancer. The absence of HRD may
be characterized by a lack of chromosomal aberrations (a detectable
variation in chromosomal DNA which may fall into at least one of
three overlapping categories: loss of heterozygosity, allelic
imbalance (e.g. telomeric allelic imbalance), or large scale
transition).
[0192] In embodiments, a method described herein treats a cancer
that is associated with deficiency in at least one gene involved in
a DNA repair pathway. Various pathways exist for DNA repair,
including base excision repair (BER), direct repair (DR), double
stranded break (DSB) repair, homologous recombination repair (HRR),
mismatch repair (MMR), nucleotide excision repair (NER), and
non-homologous end joining (NHEJ) repair; disruptions in these
pathways can lead to the development and/or growth of cancer (see
e.g. Kelley et al., Future Oncol. (2014) 10(7):1215-1237).
[0193] Exemplary genes involved in DNA repair pathways are
described in Table A.
TABLE-US-00003 TABLE A DNA Repair Genes Gene Title Gene Symbol
replication factor C (activator 1) 2, 40 kDa RFC2 X-ray repair
complementing defective repair in Chinese hamster XRCC6 cells 6 (Ku
autoantigen, 70 kDa) polymerase (DNA directed), delta 2, regulatory
subunit 50 kDa POLD2 proliferating cell nuclear antigen PCNA
replication protein A1, 70 kDa RPA1 replication protein A2, 32 kDa
RPA2 excision repair cross-complementing rodent repair deficiency,
ERCC3 complementation group 3 (xeroderma pigmentosum group B
complementing) uracil-DNA glycosylase UNG excision repair
cross-complementing rodent repair deficiency, ERCC5 complementation
group 5 (xeroderma pigmentosum, complementation group G (Cockayne
syndrome)) mutL homolog 1, colon cancer, nonpolyposis type 2 (E.
coli) MLH1 ligase I, DNA, ATP-dependent LIG1 mutS homolog 6 (E.
coli) MSH6 polymerase (DNA-directed), delta 4 POLD4 replication
factor C (activator 1) 5, 36.5 kDa RFC5 damage-specific DNA binding
protein 2, 48 kDa /// LIM homeobox 3 DDB2 /// LHX3 polymerase (DNA
directed), delta 1, catalytic subunit 125 kDa POLD1 Fanconi anemia,
complementation group G FANCG polymerase (DNA directed), beta POLB
X-ray repair complementing defective repair in Chinese hamster
XRCC1 cells 1 N-methylpurine-DNA glycosylase MPG excision repair
cross-complementing rodent repair deficiency, ERCC1 complementation
group 1 (includes overlapping antisense sequence) thymine-DNA
glycosylase TDG Fanconi anemia, complementation group A /// Fanconi
anemia, FANCA complementation group A replication factor C
(activator 1) 4, 37 kDa RFC4 replication factor C (activator 1) 3,
38 kDa RFC3 APEX nuclease (apurinic/apyrimidinic endonuclease) 2
APEX2 RADI homolog (S. pombe) RAD1 breast cancer 1, early onset
BRCA1 exonuclease 1 EXO1 flap structure-specific endonuclease 1
FEN1 mutL homolog 3 (E. coli) MLH3 O-6-methylguanine-DNA
methyltransferase MGMT RAD51 homolog (RecA homolog, E. coli) (S.
cerevisiae) RAD51 X-ray repair complementing defective repair in
Chinese hamster XRCC4 cells 4 RecQ protein-like (DNA helicase
Q1-like) RECQL excision repair cross-complementing rodent repair
deficiency, ERCC8 complementation group 8 Fanconi anemia,
complementation group C FANCC 8-oxoguanine DNA glycosylase OGG1
MRE11 meiotic recombination 11 homolog A (S. cerevisiae) MRE11A
RAD52 homolog (S. cerevisiae) RAD52 Werner syndrome WRN xeroderma
pigmentosum, complementation group A XPA Bloom syndrome BLM mutS
homolog 3 (E. coli) MSH3 polymerase (DNA directed), epsilon 2 (p59
subunit) POLE2 RAD51 homolog C (S. cerevisiae) RAD51C ligase IV,
DNA, ATP-dependent LIG4 excision repair cross-complementing rodent
repair deficiency, ERCC6 complementation group 6 ligase III, DNA,
ATP-dependent LIG3 RAD17 homolog (S. pombe) RAD17 X-ray repair
complementing defective repair in Chinese hamster XRCC2 cells 2
mutY homolog (E. coli) MUTYH replication factor C (activator 1) 1,
145 kDa /// replication factor C RFC1 (activator 1) 1, 145 kDa
breast cancer 2, early onset BRCA2 RAD50 homolog (S. cerevisiae)
RAD50 damage-specific DNA binding protein 1, 127 kDa DDB1 X-ray
repair complementing defective repair in Chinese hamster XRCC5
cells 5 (double-strand-break rejoining; Ku autoantigen, 80 kDa)
poly (ADP-ribose) polymerase family, member 1 PARP1 polymerase (DNA
directed), epsilon 3 (p17 subunit) POLE3 xeroderma pigmentosum,
complementation group C XPC mutS homolog 2, colon cancer,
nonpolyposis type 1 (E. coli) MSH2 replication protein A3, 14 kDa
RPA3 methyl-CpG binding domain protein 4 MBD4 nth endonuclease
III-like 1 (E. coli) NTHL1 PMS2 postmeiotic segregation increased 2
(S. cerevisiae) III PMS2 /// PMS2CL PMS2-C terminal-like uracil-DNA
glycosylase 2 UNG2 APEX nuclease (multifunctional DNA repair
enzyme) 1 APEX1 excision repair cross-complementing rodent repair
deficiency, ERCC4 complementation group 4 RecQ protein-like 5
RECQL5 mutS homolog 5 (E. coli) MSH5 polymerase (DNA-directed),
delta 3, accessory subunit POLD3 excision repair
cross-complementing rodent repair deficiency, ERCC2 complementation
group 2 (xeroderma pigmentosum D) RecQ protein-like 4 RECQL4 PMS1
postmeiotic segregation increased 1 (S. cerevisiae) PMS1 zinc
finger protein 276 homolog (mouse) ZFP276 polymerase (DNA
directed), epsilon POLE X-ray repair complementing defective repair
in Chinese hamster XRCC3 cells 3 nibrin NBN single-strand selective
monofunctional uracil DNA glycosylase SMUG1 Fanconi anemia,
complementation group F FANCF nei endonuclease VIII-like 1 (E.
coli) NEIL1 Fanconi anemia, complementation group E FANCE Ataxia
Telangiectasia Mutated ATM ATM and RAD3-related ATR BRCA1
associated protein-1 (ubiquitin carboxy-terminal BAP1 hydrolase)
gene BRCA1 Associated RING Domain 1 (RING-Type E3 Ubiquitin BARD1
Transferase) gene BRCA1 Interacting Protein C-Terminal Helicase 1
gene BRIP1 Partner and localizer of BRCA2 gene PALB2 RAD51 Paralog
B RAD51B RAD51 Paralog D RAD51D RAD54 Like RAD54L
[0194] In embodiments, method treats cancer in a subject exhibiting
an absence of a germline mutation in BRCA1 and BRCA2. In some
embodiments, the method treats cancer in a subject with a
platinum-sensitive tumor exhibiting an absence of a germline
mutation in BRCA1 and BRCA2.
[0195] In one aspect, the invention features a method of treating
cancer comprising: identifying a cancer patient having deficiency
in at least one gene listed in Table A.
[0196] In embodiments, a method described herein treats a cancer
that is associated with deficiency in at least one gene involved in
the homologous recombination repair (HRR) pathway. In embodiments,
a deficiency is a non-BRCA deficiency. In embodiments, a deficiency
is in two or more, three or more, four or more, five or more, six
or more, seven or more, eight or more, nine or more, ten or more,
eleven or more, twelve or more, thirteen or more, fourteen or more,
fifteen or more, sixteen or more, seventeen or more, eighteen or
more, nineteen or more, twenty or more, twenty-one or more,
twenty-two or more, twenty-three or more, twenty-four or more,
twenty-five or more, twenty-six or more, twenty-seven or more,
twenty-eight or more, twenty-nine or more, or thirty or more genes
selected from the group consisting of RFC2, XRCC6, POLD2, PCNA,
RPA1, RPA2, ERCC3, UNG, ERCC5, MLH1, LIG1, MSH6, POLD4, RFC5,
DDB2///LHX3, POLD1, FANCG, POLB, XRCC1, MPG, ERCC1, TDG, FANCA,
RFC4, RFC3, APEX2, RAD1, EXO1, FEN1, MLH3, MGMT, RAD51, XRCC4,
RECQL, ERCC8, FANCC, OGG1, MRE11A, RAD52, WRN, XPA, BLM, MSH3,
POLE2, RAD51C, LIG4, ERCC6, LIG3, RAD17, XRCC2, MUTYH, RFC1, RAD50,
DDB1, XRCC5, PARP1, POLE3, XPC, MSH2, RPA3, MBD4, NTHL1,
PMS2///PMS2CL, UNG2, APEX1, ERCC4, RECQL5, MSH5, POLD3, ERCC2,
RECQL4, PMS1, ZFP276, POLE, XRCC3, NBN, SMUG1, FANCF, NEIL1, FANCE,
ATM, ATR, BAP1, BARD1, BRIP1, PALB2, RAD51B, RAD51D, and
RAD54L.
[0197] In embodiments, cancer patients having HRR deficiencies due
to at least one of the sixteen genes listed in Table B can benefit
from methods described herein.
TABLE-US-00004 TABLE B Non-BRCA1/2 HRR Pathway Genes HRR Pathway
Genes ATM ATR BAP1 BARD1 BLM BRIP1 MRE11A NBN PALB2 RAD51 RAD51B
RAD51C RAD51D RAD52 RAD54L XRCC2
[0198] In embodiments, a deficiency in a gene involved in the HRR
pathway is identified using a pre-specified gene panel. In
embodiments, a pre-specified gene panel includes a gene listed in
Table A or Table B, or any combinations thereof. In embodiments, a
pre-specified gene panel comprises: at least one of ATM, ATR, BAP1,
BARD1, BLM, BRIP1, MRE11A, NBN, PALB2, RAD51, RAD51B, RAD51C,
RAD51D, RAD52, RAD54L, and XRCC2, and any combinations thereof; and
at least one of BRCA1 and BRCA2. In embodiments, a pre-specified
gene panel comprises: each of ATM, ATR, BAP1, BARD1, BLM, BRIP1,
MRE11A, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, RAD52, RAD54L,
and XRCC2; and at least one of BRCA1 and BRCA2. In embodiments, a
pre-specified gene panel comprises ATM, ATR, BAP1, BARD1, BLM,
BRIP1, MRE11A, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, RAD52,
RAD54L, XRCC2, BRCA1, and BRCA2.
[0199] In embodiments, the method is a mono-therapy treatment. In
other embodiments, the method is a combination therapy
treatment.
[0200] In embodiments, the method is a combination therapy
treatment in which the administration of crystalline niraparib
freebase is combined with a second therapy which induces DNA
damage. In embodiments, the second therapy comprises
radiosensitization (the administration of ionizing radiation)
and/or chemosensitization (the administration of one or more DNA
damaging agents). The DNA damaging agents may, for example, be
selected from DNA methylating agents (such as e.g. dacarbazine or
temozolomide), topoisomerase I inhibitors (such as e.g.
camptothecin, topotecan or irinotecan), and cytotoxic agents (such
as e.g. platinum-based drugs like cisplatin or carboplatin). The
administration of crystalline niraparib freebase may take place
before, during and/or after treatment with the second therapy. A
regimen for such a combination treatment could readily be
determined by a clinician.
Non-Oncological Conditions
[0201] In embodiments, the methods of the disclosure are used to
treat a condition in a subject selected from a neurological or
neurodegenerative disease, an inflammatory disease, a metabolic
disease, and a cardiovascular disease or condition. Examples of
such diseases are described by Curtin et al. (Mol Aspects Med.
(2013) 34(6):1217-1256).
[0202] In one embodiment, the method treats a subject who has
suffered from, or is at risk of suffering from stroke. In another
embodiment, the method treats a subject suffering from traumatic
brain injury. In a further embodiment, the method treats a subject
who suffers from, or is at risk of suffering from, autoimmune
diabetes.
[0203] In embodiments, the neurodegenerative disease is Parkinson's
disease. In embodiments, the inflammatory disease is asthma or
multiple sclerosis. In embodiments, the cardiovascular disease or
condition is myocardial infarction, circulatory shock, polytrauma,
or acute respiratory distress syndrome.
Administration and Dosages
[0204] Crystalline
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase as described herein can be formulated as a
pharmaceutical composition for oral, buccal, parenteral (e.g.
intravenous, intraperitoneal, intramuscular or subcutaneous),
topical, rectal or intranasal administration or in a form suitable
for administration by inhalation or insufflation. Such modes of
administration and the methods for preparing appropriate
pharmaceutical compositions are described, for example, in
Gibaldi's Drug Delivery Systems in Pharmaceutical Care (1st ed.,
American Society of 15 Health-System Pharmacists 2007).
[0205] In embodiments, an exemplary dosage regimen for niraparib is
one or more 100 mg doses taken orally once daily (e.g. two doses
equivalent to a total daily dose of 200 mg or three doses
equivalent to a total daily dose of 300 mg). Patients may be
encouraged to take their dose at approximately the same time each
day. Bedtime administration may be a potential method for managing
nausea.
[0206] In some embodiments, the methods of the invention treat
subjects with a cancer with a dosage of 1 mg, 5 mg, 10 mg, 20 mg,
25 mg, 35 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg,
225 mg, 250 mg to 275 mg, 300 mg, 325 mg, 350 mg 375 mg, 400 mg,
425 mg, 450 mg, 475 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750
mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150
mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg,
1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900
mg, 1950 mg, or 2000 mg of niraparib or pharmaceutically acceptable
salt thereof once-daily, twice-daily, or thrice-daily. In some
embodiments, the methods of the invention treat subjects with a
cancer with a dosage of 150 mg to 175 mg, 170 mg to 195 mg, 190 mg
to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg,
270 to 295 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355
mg, 350 mg to 375 mg, or 370 mg to 400 mg of niraparib or
pharmaceutically acceptable salt thereof once-daily, twice-daily,
or thrice-daily. In some embodiments, the methods of the invention
treat subjects with a cancer with a dosage of 5 mg, 7.5 mg, 10 mg,
12.5 mg, 15 mg. 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 35
mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg,
85 mg, 90 mg, 95 mg, or 100 mg of niraparib or pharmaceutically
acceptable salt thereof once-daily, twice-daily, or
thrice-daily.
[0207] In some embodiments, the methods of the invention treat
subjects with a cancer with a dosage of from about 1 mg to 5 mg, 5
mg to 10 mg, 10 mg to 20 mg, 20 mg to 25 mg, 35 mg to 50 mg, 50 mg
to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg
to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210
mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg,
290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375
mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to
550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700
mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg,
900 mg to 950 mg, 950 mg to 1000 mg, 1000 mg to 1050 mg, 1050 mg to
1100 mg, 1100 mg to 1150 mg, 1150 mg to 1200 mg, 1200 mg to about
1250 mg, 1250 mg to 1300 mg, 1300 mg to 1350 mg, 1350 mg to 1400
mg, 1400 mg to 1450 mg, 1450 mg to 1500 mg, 1500 mg to 1550 mg,
1550 mg to 1600 mg, 1600 mg to 1650 mg, 1650 mg to 1700 mg, 1700 mg
to 1750 mg, 1750 mg to 1800 mg, 1800 mg to 1850 mg, 1850 mg to 1900
mg, 1900 mg to 1950 mg, or 1950 mg to 2000 mg of niraparib or
pharmaceutically acceptable salt thereof once-daily, twice-daily,
or thrice-daily. In some embodiments, the methods of the invention
treat subjects with a cancer with a dosage of from about 5 mg to
7.5 mg, 7 mg to 9.5 mg, 9 mg to 11.5 mg, 11 mg to 13.5 mg, 13 mg to
15.5 mg, 15 mg to 17.5 mg, 17 to 19.5 mg, 19 mg to 21.5 mg, 21 mg
to 23/5 mg, 23 mg to 25.5 mg, 25 mg to 27.5 mg, 27 mg to 30 mg, 30
mg to 35 mg, 35 mg to 40 mg, 40 mg to 45 mg, 45 mg to 50 mg, 50 mg
to 55 mg, 55 mg to 60 mg, 60 to 65 mg, 65 mg to 70 mg, 70 mg to 75
mg, 75 mg to 80 mg, 80 mg to 85 mg, 85 mg to 90 mg, 90 mg to 95 mg,
or 95 mg to 100 mg of niraparib or pharmaceutically acceptable salt
thereof once-daily, twice-daily, or thrice-daily.
[0208] In a preferred embodiment, the crystalline niraparib
freebase is formulated for oral administration, e.g. in solid
form.
[0209] In a preferred embodiment, the pharmaceutical composition is
an oral composition, more preferably a solid oral dosage form, such
as e.g. a tablet, capsule, powder, granule or sachet. The oral
composition may be provided in the form of unit dosages, wherein
one or more of the unit dosages, taken together, provide(s) an
effective amount for administration to the subject.
[0210] In solid dosage forms for oral administration (e.g.
capsules, tablets, pills, dragees, powders, granules and the like),
the active ingredient is mixed with one or more pharmaceutically
acceptable excipients as described herein. In the case of capsules,
tablets, and pills, the pharmaceutical compositions can also
comprise buffering agents. Solid compositions of a similar type can
also be prepared using fillers in soft and hard-filled gelatine
capsules, and excipients such as lactose or milk sugars, as well as
high molecular weight polyethylene glycols and the like. By way of
an example, where the pharmaceutical composition is a provided in
the form of a capsule, the composition can comprise one or more
components which are combined to create a powder blend that is used
to fill the capsule. The powder blend may, for example, be filled
into gelatin capsules, such as size 0 gelatin capsules. In such
cases, the term "pharmaceutical composition" is generally to be
understood as referring to the content of the capsule, i.e. the
powder blend.
[0211] A tablet can be made by compression or moulding, optionally
with one or more accessory ingredients. Compressed tablets can be
prepared using binders (for example, gelatine or
hydroxypropylmethyl cellulose), lubricants, inert diluents,
preservatives, disintegrants (for example, sodium starch glycolate
or cross-linked sodium carboxymethyl cellulose), surface-actives,
and/or dispersing agents. Molded tablets can be made by molding in
a suitable machine a mixture of the powdered active ingredient
moistened with an inert liquid diluent. The tablets and other solid
dosage forms, such as dragees, capsules, pills, and granules, can
optionally be scored or prepared with coatings and shells, such as
enteric coatings and other coatings well known in the art.
[0212] In embodiments, a solid dosage form for administering a
therapeutically effective amount of niraparib to a subject
comprises crystalline naraparib freebase as described herein in an
amount of from about 1 mg to about 1000 mg. In embodiments, the
solid dosage form comprises from about 25 mg to about 750 mg of
crystalline naraparib freebase, e.g. from about 50 mg to about 500
mg, from about 60 mg to about 400 mg, or from about 75 mg to about
300 mg. In other embodiments, the solid dosage form comprises from
about 50 to about 300 mg of crystalline naraparib freebase. In
embodiments, the solid dosage form comprises about 50 mg, 75 mg,
100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300
mg, 325 mg or 350 mg of crystalline naraparib freebase. In
embodiments, a solid dosage form for administering a
therapeutically effective amount of niraparib to a subject
comprises crystalline naraparib freebase as described herein in an
amount of greater than about 100 mg. In embodiments, the solid
dosage form comprises greater than about 120 mg, 140 mg, 160 mg,
180 mg, 200 mg, 220 mg, 240 mg, 260 mg or 280 mg.
[0213] In embodiments, the loading of crystalline naraparib
freebase (e.g. the above-mentioned amounts) in the solid dosage
form is such that at least 25% of the weight of the pharmaceutical
composition is the crystalline naraparib freebase. In embodiments,
the loading of crystalline naraparib freebase is at least 30%, 35%,
40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or 80% by weight of the
pharmaceutical composition.
[0214] In embodiments, the solid dosage form is presented as one,
two or three unit dosages. In embodiments, the solid oral dosage
form is administered one, two, or three times a day such as to
provide a therapeutically effective amount of crystalline naraparib
freebase for use in a method as described herein. In a preferred
embodiment, the solid dosage form is presented as a single unit
dosage which is administered once daily, i.e. it provides a
therapeutically effective daily amount of crystalline naraparib
freebase (such as e.g. about 300 mg). In another preferred
embodiment, the solid dosage form is presented as two unit dosages
which are administered together or separately, i.e. they provide
between them a therapeutically effective daily amount of
crystalline naraparib freebase (such as e.g. about 150 mg per unit
dosage).
[0215] For buccal administration, the composition may take the form
of tablets or lozenges formulated in a conventional manner.
[0216] In some embodiments, the pharmaceutical compositions are
administered by non-oral means such as by topical application,
transdermal application, injection, and the like. In related
embodiments, the pharmaceutical compositions are administered
parenterally by injection, infusion, or implantation (e.g.
intravenous, intramuscular, intra-arterial, subcutaneous, and the
like). In each case, it is preferred that the pharmaceutical
composition is stored and/or used in a solid form, so as to take
advantage of the properties of crystalline naraparib freebase.
[0217] The pharmaceutical compositions can be suitable for the
preparation of injectable formulations for parenteral
administration, including using conventional catheterisation
techniques or infusion. Formulations for injection may be presented
in unit dosage form, e.g. in ampules or in multi-dose containers,
with an added preservative. The compositions may take such forms as
suspensions or emulsions in oily or aqueous vehicles, and may
contain a formulating agent such as a suspending, stabilising
and/or dispersing agent recognised by those of skill in the art.
Alternatively, the active ingredient may be in powder form for
reconstitution with a suitable vehicle, e.g. sterile pyrogen-free
water, before use.
[0218] The pharmaceutical compositions can be suitable for the
preparation of sterile injectable formulations. Those formulations
can be sterilised by, for example, filtration through a
bacteria-retaining filter, or by incorporating sterilising agents
in the form of sterile solid compositions which can be dissolved in
sterile water, or some other sterile injectable medium immediately
before use. To prepare such a composition, the active ingredient is
dissolved or suspended in a parenterally acceptable liquid vehicle.
Exemplary vehicles and solvents include, but are not limited to,
water, water adjusted to a suitable pH by addition of an
appropriate amount of hydrochloric acid, sodium hydroxide or a
suitable buffer, 1,3-butanediol, Ringer's solution and isotonic
sodium chloride solution. The pharmaceutical composition can also
contain one or more preservatives, for example, methyl, ethyl or
n-propyl p-hydroxybenzoate. To improve solubility, a dissolution
enhancing or solubilising agent can be added or the solvent can
contain 10-60% w/w of propylene glycol or the like.
[0219] The pharmaceutical compositions can contain one or more
pharmaceutically acceptable sterile isotonic aqueous or nonaqueous
solutions, dispersions, suspensions or emulsions, or sterile
powders, which can be reconstituted into sterile injectable
solutions or dispersions just prior to use. Such pharmaceutical
compositions can contain antioxidants; buffers; bacteriostats;
solutes, which render the formulation isotonic with the blood of
the intended recipient; suspending agents; thickening agents;
preservatives; and the like.
[0220] Examples of suitable aqueous and nonaqueous carriers, which
can be employed in the pharmaceutical compositions of the invention
include water, ethanol, polyols (such as glycerol, propylene
glycol, polyethylene glycol, and the like), and suitable mixtures
thereof, vegetable oils, such as olive oil, and injectable organic
esters, such as ethyl oleate. Proper fluidity can be maintained,
for example, by the use of coating materials, such as lecithin, by
the maintenance of the required particle size in the case of
dispersions, and by the use of surfactants. In some embodiments, in
order to prolong the effect of an active ingredient, it is
desirable to slow the absorption of the compound from subcutaneous
or intramuscular injection. This can be accomplished by the use of
a liquid suspension of crystalline material having poor water
solubility. The rate of absorption of the active ingredient then
depends upon its rate of dissolution which, in turn, can depend
upon crystal size and crystalline form. Alternatively, delayed
absorption of a parenterally-administered active ingredient is
accomplished by dissolving or suspending the compound in an oil
vehicle. In addition, prolonged absorption of the injectable
pharmaceutical form can be brought about by the inclusion of agents
that delay absorption such as aluminium monostearate and
gelatine.
[0221] Controlled release parenteral compositions can be in form of
aqueous suspensions, microspheres, microcapsules, magnetic
microspheres, oil solutions, oil suspensions, emulsions, or the
active ingredient can be incorporated in biocompatible carrier(s),
liposomes, nanoparticles, implants or infusion devices. Materials
for use in the preparation of microspheres and/or microcapsules
include, but are not limited to, biodegradable/bioerodible polymers
such as polyglactin, poly-(isobutyl cyanoacrylate),
poly(2-hydroxyethyl-L-glutamine) and poly(lactic acid).
Biocompatible carriers which can be used when formulating a
controlled release parenteral formulation include carbohydrates
such as dextrans, proteins such as albumin, lipoproteins or
antibodies. Materials for use in implants can be non-biodegradable,
e.g. polydimethylsiloxane, or biodegradable such as, e.g.,
poly(caprolactone), poly(lactic acid), poly(glycolic acid) or
poly(ortho esters).
[0222] For topical administration, crystalline niraparib freebase
may be formulated as an ointment or cream. Crystalline niraparib
freebase may also be formulated in rectal compositions such as
suppositories or retention enemas, e.g. containing conventional
suppository bases such as cocoa butter or other glycerides.
[0223] For intranasal administration or administration by
inhalation, crystalline niraparib freebase may be conveniently
delivered in the form of a solution or suspension from a pump spray
container that is squeezed or pumped by the patient or as an
aerosol spray presentation from a pressurised container or a
nebulizer, with the use of a suitable propellant, e.g.
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
the case of a pressurised aerosol, the dosage unit may be
determined by providing a valve to deliver a metered amount. The
pressurised container or nebulizer may contain a solution or
suspension. Capsules and cartridges (made, for example, from
gelatine) for use in an inhaler or insufflator may be formulated
containing a powder mix of crystalline niraparib freebase and a
suitable powder base such as lactose or starch.
[0224] In other aspects, the invention provides a dosage form or
pharmaceutical composition as described herein for use in therapy,
e.g. for use in a method as defined herein.
[0225] In other aspects, the invention provides an article of
manufacture (e.g. a kit) comprising multiple unit doses of a
pharmaceutical composition as described herein in a sealed
container with written instructions for use. In embodiments, the
article of manufacture further comprises an induction seal, a
desiccant, or a combination thereof.
Combination Therapies
[0226] Crystalline forms of niraparib freebase described herein can
be useful as monotherapy or in combination therapy with the
administration of one or more additional therapeutic agents or
lines of therapy.
[0227] For example, a crystalline form of niraparib freebase
described herein can be administered in combination with surgery, a
radiotherapy, a chemotherapy, an immunotherapy, an anti-angiogenic
agent, or an anti-inflammatory agent.
[0228] Where a crystalline form of niraparib freebase is
administered in combination with one or more different therapeutic
agents (e.g. as described herein), administering of the crystalline
form of niraparib freebase can occur sequentially with the
administering of the one or more different therapeutic agents. For
example, administration of the crystalline form of niraparib
freebase occurs before administration of the one or more different
therapeutic agents. In embodiments, administration of the
crystalline form of niraparib freebase occurs after administration
of the one or more different therapeutic agents. In other
embodiments, administering of the crystalline form of niraparib
freebase occurs simultaneously with the administering of the one or
more different therapeutic agents.
[0229] In embodiments, a crystalline form of niraparib freebase
described herein is administered in combination with one or more
immune checkpoint inhibitors. In embodiments, a checkpoint
inhibitor is an agent capable of inhibiting any of the following:
PD-1 (e.g. inhibition via anti-PD-1, anti-PD-L1, or anti-PD-L2
therapies), CTLA-4, TIM-3, TIGIT, LAGs (e.g. LAG-3), CEACAM (e.g.
CEACAM-1, -3 and/or -5), VISTA, BTLA, LAIR1, CD160, 2B4, CD80,
CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR,
A2aR, MHC class I, MHC class II, GALS, adenosine, TGFR (e.g. TGFR
beta), B7-H1, B7-H4 (VTCN1), OX-40, CD137, CD40, IDO, or CSF-1R. In
embodiments, a checkpoint inhibitor is a small molecule, a nucleic
acid, a polypeptide (e.g. an antibody), a carbohydrate, a lipid, a
metal, or a toxin. In embodiments, a checkpoint inhibitor is an
antibody, an antibody conjugate, or an antigen-binding fragment
thereof.
[0230] In embodiments, an immune checkpoint inhibitor is a PD-1
inhibitor. In embodiments, a PD-1 inhibitor is a small molecule, a
nucleic acid, a polypeptide (e.g. an antibody, an antibody
conjugate, or an antigen-binding fragment thereof), a carbohydrate,
a lipid, a metal, or a toxin. In embodiments, a PD-1 inhibitor is a
PD-1 binding agent (e.g. an antibody, an antibody conjugate, or an
antigen-binding fragment thereof). In embodiments, a PD-1 binding
agent is an antibody, an antibody conjugate, or an antigen-binding
fragment thereof. In embodiments, a PD-1 binding agent is TSR-042,
nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab,
PDR-001, tislelizumab (BGB-A317), cemiplimab (REGN2810),
LY-3300054, JNJ-63723283, MGA012, BI-754091, IBI-308, camrelizumab
(HR-301210), BCD-100, JS-001, CX-072, BGB-A333, AMP-514
(MEDI-0680), AGEN-2034, CS1001, Sym-021, SHR-1316, PF-06801591,
LZM009, KN-035, AB122, genolimzumab (CBT-501), FAZ-053, CK-301, AK
104, or GLS-010. In embodiments, a PD-1 inhibitor is a PD-L1 or
PD-L2 binding agent such as durvalumab, atezolizumab, avelumab,
BGB-A333, SHR-1316, FAZ-053, CK-301, or, PD-L1 millamolecule, or
derivatives thereof. In embodiments, an anti-PD-1 agent is
pembrolizumab. In embodiments, an anti-PD-1 agent is nivolumab. In
some embodiments, a PD-1 antibody agent is as disclosed in
International Patent Application Publication Nos. WO2014/179664, WO
2018/085468, or WO 2018/129559. In further embodiments, a PD-1
antibody agent is administered according to a method disclosed in
International Patent Application Publication Nos. WO2014/179664, WO
2018/085468, or WO 2018/129559. In embodiments, an anti-PD-1 agent
is TSR-042.
[0231] In embodiments, an immune checkpoint inhibitor is a TIM-3
inhibitor. In embodiments, a TIM-3 inhibitor is a small molecule, a
nucleic acid, a polypeptide (e.g. an antibody, an antibody
conjugate, or an antigen-binding fragment thereof), a carbohydrate,
a lipid, a metal, or a toxin. In embodiments, a TIM-3 inhibitor is
a TIM-3 binding agent (e.g. an antibody, an antibody conjugate, or
an antigen-binding fragment thereof). In embodiments, a TIM-3
binding agent is an antibody, an antibody conjugate, or an
antigen-binding fragment thereof. In some embodiments, a TIM-3
antibody agent is MBG453, LY3321367, Sym023, TSR-022, or a
derivative thereof. In some embodiments, a TIM-3 antibody agent is
as disclosed in International Patent Application Publication Nos.
WO2016/161270, WO 2018/085469, or WO 2018/129553. In some
embodiments, a TIM-3 antibody agent is administered as disclosed in
International Patent Application Publication Nos. WO2016/161270, WO
2018/085469, or WO 2018/129553. In some embodiments, a TIM-3
antibody agent is TSR-022.
[0232] In embodiments, an immune checkpoint inhibitor is a LAG-3
inhibitor. In embodiments, an anti-LAG-3 agent is an antibody, an
antibody conjugate, or an antigen-binding fragment thereof. In
embodiments, an anti-LAG-3 agent is a small molecule, a nucleic
acid, a polypeptide (e.g. an antibody), a carbohydrate, a lipid, a
metal, or a toxin. In embodiments, an anti-LAG-3 agent is a small
molecule. In embodiments, an anti-LAG-3 agent is a LAG-3 binding
agent. In embodiments, an anti-LAG-3 agent is an antibody, an
antibody conjugate, or an antigen-binding fragment thereof. In
embodiments, an anti-LAG-3 agent is IMP321, relatlimab
(BMS-986016), BI 754111, GSK2831781 (IMP-731), Novartis LAG525
(IMP701), REGN3767, MK-4280, MGD-013, GSK-2831781, FS-118,
XmAb22841, INCAGN-2385, FS-18, ENUM-006, AVA-017, AM-0003, Avacta
PD-L1/LAG-3 bispecific affamer, iOnctura anti-LAG-3 antibody, Arcus
anti-LAG-3 antibody, or Sym022, or TSR-033. In some embodiments, a
LAG-3 antibody agent is as disclosed in International Patent
Application Publication WO2016/126858 or in in International Patent
Application No. PCT/US18/30027. In some embodiments, a LAG-3
antibody agent is administered as disclosed in International Patent
Application Publication WO2016/126858 or in in International Patent
Application No. PCT/US18/30027. In embodiments, a LAG-3 antibody
agent is TSR-033.
[0233] In embodiments, a niraparib tablet composition is
administered in combination with a PD-1 inhibitor (e.g. TSR-042,
pembrolizumab, or nivolumab). In embodiments, a niraparib tablet
composition is administered in combination with a TIM-3 inhibitor
(e.g. TSR-022). In embodiments, a niraparib tablet composition is
administered in combination with a LAG-3 inhibitor (e.g. TSR-033).
In embodiments, a niraparib tablet composition is administered in
combination with a PD-1 inhibitor (e.g. TSR-042, pembrolizumab, or
nivolumab) and a TIM-3 inhibitor (e.g. TSR-022). In embodiments, a
niraparib tablet composition is administered in combination with a
PD-1 inhibitor (e.g. TSR-042, pembrolizumab, or nivolumab) and a
LAG-3 inhibitor (e.g. TSR-033). In embodiments, a niraparib tablet
composition is administered in combination with a TIM-3 inhibitor
(e.g. TSR-022) and a LAG-3 inhibitor (e.g. TSR-033). In
embodiments, a niraparib tablet composition is administered in
combination with a PD-1 inhibitor (e.g. TSR-042, pembrolizumab, or
nivolumab), a TIM-3 inhibitor (e.g. TSR-022), and a LAG-3 inhibitor
(e.g. TSR-033).
[0234] In embodiments, a niraparib tablet composition is
administered in combination with one or more chemotherapy
agents.
[0235] In embodiments, a niraparib tablet composition is
administered in combination with a platinum-based chemotherapy
agent (e.g. one or more of cisplatin, carboplatin, oxaliplatin,
nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin,
and satraplatin).
[0236] In embodiments, a niraparib tablet composition is
administered in combination with a chemotherapy agent that is
aminoglutethimide, amsacrine, anastrozole, asparaginase, bcg,
bicalutamide, bleomycin, buserelin, busulfan, campothecin,
capecitabine, carboplatin, carmustine, chlorambucil, cisplatin,
cladribine, clodronate, colchicine, cyclophosphamide, cyproterone,
cytarabine, dacarbazine, dactinomycin, daunorubicin, dienestrol,
diethylstilbestrol, docetaxel, doxorubicin, epirubicin, estradiol,
estramnustine, etoposide, exemestane, filgrastim, fludarabine,
fludrocortisone, fluorouracil, fluoxymesterone, flutamide,
gemcitabine, genistein, goserelin, hydroxyurea, idarubicin,
ifosfamide, imatinib, interferon, irinotecan, ironotecan,
letrozole, leucovorin, leuprolide, levamisole, lomustine,
mechlorethamine, medroxyprogesterone, megestrol, melphalan,
mercaptopurine, mesna, methotrexate, mitomycin, mitotane,
mitoxantrone, nilutamide, nocodazole, octreotide, oxaliplatin,
paclitaxel, pamidronate, pentostatin, plicamycin, porfimer,
procarbazine, raltitrexed, rituximab, streptozocin, suramin,
tamoxifen, temozolomide, teniposide, testosterone, thioguanine,
thiotepa, titanocene dichloride, topotecan, trastuzumab, tretinoin,
vinblastine, vincristine, vindesine, or vinorelbine.
[0237] In embodiments, a niraparib tablet composition is
administered in combination with a second agent that is a
regulatory T cell (Treg) inhibitory agent, a macrophage inhibitory
agent, an antigen specific immune response enhancer agent, antigen
specific immune response enhancer agent, anti-angiogenic agent, a
chemotherapy agent or a combination thereof. In embodiments, a
second agent is any second agent described in International
Application No. PCT/US18/33437, herein incorporated by reference in
its entirety.
[0238] In embodiments, a macrophage inhibitory agent is selected
from the group consisting of a macrophage recruitment inhibitory
agent (e.g. an anti-CCL2/CCR2 agent, an anti-IL6 agent, an
anti-M-CSFR agent, and combinations thereof), an M2 macrophage
antisurvival agent, an M1 macrophage enhancing agent, an M2 to M1
polarizing agent, a macrophage activity inhibitor agent and
combinations thereof. In embodiments, a macrophage recruitment
inhibitory agent is selected from the group consisting of
trabectedin, RS102895, PF-04136309, CNT0888, MLN1202, siltuximab,
JNJ-28312141, GW2580, IMC-CS4 (LY3022855), emactuzumab, AMG820,
pexidartinib, linifanib, OSI-930, CEP-32496, PLX7846, BLZ945,
ARRY-382, JNJ-40346527, MCS110, PLX3397, PLX6134, PD-0360324,
FPA008, and combinations thereof. In embodiments, a M2 macrophage
antisurvival agent is selected from the group consisting of an MMP
inhibitor, clodronate, zoledronic acid, dichloromethylene
bisphosphonate, trabectedin, dasatinib, retinoic acid, attenuated
bacteria (e.g. Shigella flexneri, Salmonella typhimurium, Listeria
monocytogens, Chlamydia psittaci, Legionella pneumophila), and
combinations thereof. In embodiments, a M1 macrophage enhancing
agent or the M2 to M1 polarizing agent is selected from the group
consisting of an anti-CD40 agent, an anti-IL-10R agent, a CD47
antagonist (e.g. Hu5F9-G4, CC-90002, and CD47-Fc fusion protein
TTI-621), PolyI:C, LPS, monophosphoryl A, imiquimod, R-848,
CpG-ODN, IFN-.alpha., IFN-.beta., IFN-.gamma., GM-CSF, IL-12, IL-2,
IL-15, T.alpha.1, ibrutinib, EF-022 and combinations thereof. In
embodiments, macrophage activity inhibitory agent is selected from
the group consisting of a STAT3 inhibitor, a STAT6 inhibitor, or an
anti-tumor drug agent (e.g. a macrophage activity inhibitory agent
is WP1066, sunitinib, sorafenib, STA-21, IS3 295, S3I-M2001,
AS1517499, leflunomide, TMC-264, histidine-rich glycoprotein (HRG),
copper chelate (CuNG), 5,6-dimethylxanthenone-4-acetic acid
(MDXAA), vadimezan (ASA404), cisplatin, silibinin, proton pump
inhibitor pantoprazole (PPZ), or CNI-1493, or combinations
thereof). In embodiments, a macrophage inhibitor agent is an
anti-IL-1.alpha. agent (e.g. xilonix).
[0239] In embodiments a regulatory T cell (Treg) inhibitory agent
is selected from the group consisting of a Treg ablating agent, a
Treg migration inhibitor agent, a Treg function inhibitor agent,
and combinations thereof. In embodiments, a Treg ablating agent is
selected from the group consisting of cyclophosphamide, paclitaxel,
imatinib, sunitinib, sorafenib, dasatinib, temozolomide,
daclizumab, denileukin diftitox, and combinations thereof. In
embodiments, a Treg migration inhibitor agent is selected from the
group consisting of AMD3100, mogamulizumab, casuarinin, fucoidan,
and combinations thereof. In embodiments, a Treg function inhibitor
agent is selected from the group consisting of an anti-CTLA4 agent
(e.g. ipilimumab, tremelimumab), an anti-OX40 agent, an anti-GITR
agent, an adenosine receptor antagonist (e.g. caffeine,
theophylline, theobromine, and 8-phenylxanthines), P60, and
combinations thereof.
[0240] In embodiments, an antigen specific immune response enhancer
agent is selected from the group consisting of an anti-PD-1 agent,
an anti-PD-L1 agent, a GITR (glucocorticoid-induced TNFR-related
protein) stimulating agent, an anti-CTLA4 agent, an anti-TIM-3
agent, an anti-LAG-3 agent, an anti-IDO agent, an agent that
enhances tumor antigen presentation (e.g. personalized cancer
vaccine, autologous antigen presenting cell, autologous dendritic
cells, artificial antigen presenting cell), a chemokine signaling
agent, an anti-VEGF agent, a cytokine signal stimulating agent, and
combinations thereof.
[0241] In embodiments, a GITR stimulating agent is selected from
the group consisting of DTA-1, mGITRL, pGITRL, and combinations
thereof. In embodiments, an anti-CTLA4 agent is selected from the
group consisting of ipilimumab, tremelimumab, and combinations
thereof. In embodiments, a chemokine signaling agent is selected
from the group consisting of CXCL16, a CXCR6 chemokine receptor
(CD186) agonist, and combinations thereof. In embodiments, an
anti-VEGF agent is selected from the group consisting of
bevacizumab, pazopanib, sunitinib, sorafenib, axitinib, ponatinib,
regorafenib, cabozantinib, vandetanib, ramucirumab, lenvatinib,
ziv-aflibercept, and combinations thereof. In embodiments, a
cytokine signal stimulating agent is an interleukin or an
interferon. In embodiments, an interleukin is selected from the
group consisting of IL-2, IL-1, IL-7, IL-15, IL-12, IL-18 and
combinations thereof. In embodiments, an interferon is IFN
alpha.
[0242] In embodiments, an antigen specific immune response enhancer
agent is selected from the group consisting of a flavonoid (e.g.
flavonoid glycoside), lidocaine, lamotrigine, sulfamethoxazole,
phenytoin, carbamazepine, sulfamethoxazole, phenytoin, allopurinol,
paracetamol, mepivacaine, p-phenylenediamine, ciprofloxacin and
moxifloxacin.
[0243] In embodiments, an anti-angiogenic agent is TNP-470,
platelet factor 4, thrombospondin-1, tissue inhibitors of
metalloproteases (TIMP1 and TIMP2), prolactin, angiostatin,
endostatin, bFGF soluble receptor, transforming growth factor beta,
interferon alpha, soluble KDR and FLT-1 receptors, placental
proliferin-related protein, and combinations thereof. In
embodiments, an anti-angiogenic agent reduces the production of a
pro-angiogenic factor, inhibits an interaction between a
pro-angiogenic factor and a pro-angiogenic receptor, inhibits a
function of a pro-angiogenic factor, inhibits a function of a
pro-angiogenic factor receptor, reduces of blood flow by disruption
of blood vessels, inhibits vessel sprouting, or any combinations
thereof. In embodiments, an anti-angiogenic agent is a small
organic or inorganic molecule; a saccharine; an oligosaccharide; a
polysaccharide; a carbohydrate; a peptide; a protein; a peptide
analog; a peptide derivative; a lipid; an antibody; an antibody
fragment, a peptidomimetic; a nucleic acid; a nucleic acid analog;
a nucleic acid derivative; an extract made from biological
materials; a naturally occurring or synthetic composition; a metal;
a toxin; or any combination thereof. In embodiments, an
anti-angiogenic agent is selected from the group consisting of
bevacizumab, itraconazole, carboxyamidotriazole, TNP-470,
fumagillin, CM101, IL-12, platelet factor-4, suramin, SU5416,
thrombospondin, angiostatic steroids, heparin, cartilage-derived
angiogenesis inhibitory factor, matrix metalloproteinase inhibitor,
angiostatin, endostatin, 2-methoxyestradiol, tecogalan,
tetrathiomolybdate, thrombospondin, thalidomide, prolactin,
.alpha.V.beta.3 inhibitor, lenalidomide, linomide, ramucirumab,
tasquinimod, ranibizumab, sorafenib, sunitinib, pazopanib,
everolimus, tissue inhibitors of metalloproteases (TIMP1 and
TIMP2), bFGF soluble receptor, transforming growth factor beta,
interferon alpha, soluble KDR and FLT-1 receptors, placental
proliferin-related protein, pazopanib, sunitinib, sorafenib,
axitinib, ponatinib, cabozantinib, regorafenib, vandetanib,
lenvatinib, semaxanib, SU6668, vatalanib, tivozanib, cediranib,
protamine, heparin, steroids, ascorbic acid ethers, sulfated
polysaccharide DS 4152, fumagillin, AGM 12470, neovastat,
R04929097, MRK-003, MK-0752, PF03084014, MEDI0639, curcumin,
3,3'-diindolylmethane (DIM), resveratrol,
3,5-bis(2,4-difluorobenzylidene)-4-piperidone (DiFiD) and
epigallocatechin-3-gallate (EGCG), honokiol, OMP-21M18,
navicixizumab (OMP-305B83), Flt.sub.2-11, CBO-P11, Je-11, V1, and
any combination thereof.
[0244] In some embodiments, an anti-angiogenic agent inhibits a
DLL4/Notch signaling pathway.
[0245] In some embodiments, the angiogenesis inhibitor inhibiting
the DLL4/Notch signaling pathway is a gamma-secretase inhibitor
(GSI), a siRNA, or a monoclonal antibody against a Notch receptor
or ligand. In some embodiments, an anti-angiogenic agent is
selected from the group consisting of R04929097, MRK-003, MK-0752,
PF03084014, MEDI0639, curcumin, 3,3'-diindolylmethane (DIM),
resveratrol, 3,5-bis(2,4-difluorobenzylidene)-4-piperidone (DiFiD)
and epigallocatechin-3-gallate (EGCG), honokiol, and any
combination thereof.
[0246] In some embodiments, an anti-angiogenic agent inhibits a
vascular endothelial growth factor (VEGF)/vascular endothelial
growth factor receptor (VEGFR) pathway. In some embodiments, an
anti-angiogenic agent is selected from the group consisting of Akt
Inhibitor, calcineurin autoinhibitory peptide, ET-18-OCH3, Go 6983,
NG-Nitro-L-arginine methyl ester, p21-activated kinase Inhibitor,
cPLA2.alpha. inhibitor, PI-103, PP2, SB 203580, U0126, VEGFR
tyrosine kinase inhibitor V, VEGFR2 kinase inhibitor VI, VEGFR2
kinase inhibitor III, ZM 336372, and any combination thereof.
[0247] In some embodiments, an anti-angiogenic agent inhibits a
VEGF family protein and/or a VEGFR family protein. In some
embodiments, the VEGF family protein comprises VEGF-A, VEGF-B,
VEGF-C, VEGF-D, P1GF (placental growth factor), VEGF-E (Orf-VEGF),
Trimeresurus flavoviridis svVEGF, or any combination thereof. In
some embodiments, an anti-angiogenic agent is bevacizumab,
ranibizumab, OPT-302, ziv-aflibercept, or any combinations thereof.
In some embodiments, an anti-angiogenic agent is Flt2-11, CBO-P11,
Je-11, V1, or any combination thereof. In some embodiments, an
anti-angiogenic agent is pazopanib, sunitinib, sorafenib, axitinib,
ponatinib, cabozantinib, regorafenib, vandetanib, lenvatinib,
semaxanib, SU6668, vatalanib, tivozanib, cediranib, or any
combination thereof.
[0248] Having been generally described herein, the follow
non-limiting examples are provided to further illustrate this
invention.
Exemplary Aspects and Embodiments of the Invention
[0249] Exemplary aspects and embodiments of the invention are
described herein and include items 1-40. [0250] Item 1. Crystalline
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase. [0251] Item 2. A crystalline Form I of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase. [0252] Item 3. The crystalline Form I of
niraparib freebase according to item 2, having an X-ray powder
diffraction (XRPD) pattern comprising a peak at 18.7.+-.0.2.degree.
2.theta.. [0253] Item 4. The crystalline Form I of niraparib
freebase according to item 2 or item 3, having an XRPD pattern
comprising peaks at 18.7 and 22.5.+-.0.2.degree. 2.theta.. [0254]
Item 5. The crystalline Form I of niraparib freebase according to
item 2 or item 3, having an XRPD pattern comprising peaks at 18.7
and 19.6.+-.0.2.degree. 2.theta.. [0255] Item 6. The crystalline
Form I of niraparib freebase according to any one of items 2 to 5,
having an XRPD pattern comprising peaks at 18.7, 19.6 and
22.5.+-.0.2.degree. 2.theta.. [0256] Item 7. The crystalline Form I
of niraparib freebase according to any one of items 2 to 6, having
an XRPD pattern comprising one or more peaks at 16.9, 18.7, 19.6,
21.6 and 22.5.+-.0.2.degree. 2.theta.. [0257] Item 8. The
crystalline Form I of niraparib freebase according to any one of
items 2 to 7, having an XRPD pattern comprising at least two peaks
at 16.9, 18.7, 19.6, 21.6 and 22.5.+-.0.2.degree. 2.theta.. [0258]
Item 9. The crystalline Form I of niraparib freebase according to
any one of items 2 to 8, having an XRPD pattern comprising at least
three peaks at 16.9, 18.7, 19.6, 21.6 and 22.5.+-.0.2.degree.
2.theta.. [0259] Item 10. The crystalline Form I of niraparib
freebase according to any one of items 2 to 9, having an XRPD
pattern comprising at least four peaks at 16.9, 18.7, 19.6, 21.6
and 22.5.+-.0.2.degree. 2.theta.. [0260] Item 11. The crystalline
Form I of niraparib freebase according to any one of items 2 to 10,
having an XRPD pattern comprising peaks at 16.9, 18.7, 19.6, 21.6
and 22.5.+-.0.2.degree. 2.theta.. [0261] Item 12. The crystalline
Form I of niraparib freebase according to any one of items 2 to 11,
having an XRPD pattern comprising one or more peaks at 15.6, 16.5,
22.4, 23.2, and 29.3.+-.0.2.degree. 2.theta.. [0262] Item 13. The
crystalline Form I of niraparib freebase according to any one of
items 2 to 12, having an XRPD pattern comprising at least two peaks
at 15.6, 16.5, 22.4, 23.2, and 29.3.+-.0.2.degree. 2.theta.. [0263]
Item 14. The crystalline Form I of niraparib freebase according to
any one of items 2 to 13, having an XRPD pattern comprising at
least three peaks at 15.6, 16.5, 22.4, 23.2, and
29.3.+-.0.2.degree. 2.theta.. [0264] Item 15. The crystalline Form
I of niraparib freebase according to any one of items 2 to 14,
having an XRPD pattern comprising at least four peaks at 15.6,
16.5, 22.4, 23.2, and/or 29.3.+-.0.2.degree. 2.theta.. [0265] Item
16. The crystalline Form I of niraparib freebase according to any
one of items 2 to 15, having an XRPD pattern comprising peaks at
15.6, 16.5, 22.4, 23.2, and 29.3.+-.0.2.degree. 2.theta.. [0266]
Item 17. The crystalline Form I of niraparib freebase according to
any one of items 2 to 16, having an XRPD pattern comprising peaks
at 15.6, 16.5, 16.9, 18.7, 19.6, 21.6, 22.4, 22.5, 23.2 and
29.3.+-.0.2.degree. 2.theta.. [0267] Item 18. The crystalline Form
I of niraparib freebase according to any one of items 2 to 17,
having an XRPD pattern comprising peaks with the 2.theta. values,
and optionally also relative intensities, according to the
following table:
TABLE-US-00005 [0267] Pos. [.degree.2.theta.] Rel. Int. [%] 8.4 3
12.2 8 12.8 1 13.7 1 15.6 19 16.5 25 16.9 27 17.4 7 18.0 2 18.7 100
19.6 37 20.0 7 21.6 28 22.4 23 22.5 38 23.2 21 24.4 2 25.0 6 25.2 9
25.7 6 27.3 2 27.9 8 29.3 13 30.4 2 31.0 3 32.0 2 32.7 1 33.2 3
33.8 3 34.7 2
[0268] Item 19. The crystalline niraparib freebase according to any
one of items 1 to 18, characterised by an XRPD pattern
substantially as shown in FIG. 1. [0269] Item 20. The crystalline
niraparib freebase according to any one of items 1 to 19,
characterised by an infrared (IR) spectrum comprising a peak at
about 1652 cm.sup.-1 and a peak at about 1608 cm.sup.-1. [0270]
Item 21. The crystalline niraparib freebase according to any one of
items 1 to 20, characterised by an infrared (IR) spectrum
substantially as shown in FIG. 4. [0271] Item 22. The crystalline
niraparib freebase according to any one of items 1 to 21,
characterised by a Raman spectrum comprising peaks at about 960.3,
1457.5 and 1607.0 cm.sup.-1. [0272] Item 23. The crystalline
niraparib freebase according to any one of items 1 to 22,
characterised by a Raman spectrum substantially as shown in FIG. 5.
[0273] Item 24. The crystalline niraparib freebase according to any
one of items 1 to 23, characterised by a melting point of about
185-195.degree. C. [0274] Item 25. The crystalline niraparib
freebase according to any one of items 1 to 24, characterised by a
DTA thermogram substantially as shown in FIG. 6. [0275] Item 26.
The crystalline niraparib freebase according to any one of items 1
to 25, characterised by a DSC thermogram substantially as shown in
FIG. 7. [0276] Item 27. The crystalline niraparib freebase
according to any one of items 1 to 26, characterised by adsorbing
less than about 1% by weight of water up to about 90% relative
humidity at about 25.degree. C. [0277] Item 28. A crystalline Form
II, III, IV, or V of
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
(niraparib) freebase. [0278] Item 29. A composition comprising the
crystalline niraparib freebase of any one of items 1 to 28, wherein
the composition is substantially free of amorphous niraparib, a
pharmaceutically acceptable salt of niraparib, and/or any other
solid form of niraparib or niraparib salt. [0279] Item 30. The
composition of item 29, wherein less than about 10% (or less than
about 5%) of the total niraparib in the composition is in the form
of said amorphous niraparib, said pharmaceutically acceptable salt
of niraparib, and/or any other solid form of niraparib or niraparib
salt. [0280] Item 31. A pharmaceutical composition comprising the
crystalline niraparib freebase of any one of items 1 to 28, or the
composition of item 29 or 30, and at least one pharmaceutically
acceptable excipient. [0281] Item 32. The crystalline niraparib
freebase of any one of items 1 to 28, the composition of item 29 or
30, or the pharmaceutical composition of item 31, for use in
therapy. [0282] Item 33. Use of the crystalline niraparib freebase
of any one of items 1 to 28, or the composition of item 29 or 30,
or the pharmaceutical composition of item 31, in the manufacture of
a medicament. [0283] Item 34. A method of treating cancer, stroke,
autoimmune diabetes, a neurological disease, an inflammatory
disease, a metabolic disease or a cardiovascular disease in a
subject, the method comprising administering to the subject an
effective amount of the crystalline niraparib freebase of any one
of items 1 to 28, or the composition of item 29 or 30, or the
pharmaceutical composition of item 31. [0284] Item 35. The method
according to item 34, wherein said method is a method of treating
cancer. [0285] Item 36. The method according to item 35, wherein
said cancer is associated with BRCA1 and/or BRCA2 mutations. [0286]
Item 37. The method according to item 35 or 36, wherein said cancer
is associated with a mutation in ATM, ATR, BAP1, BARD1, BLM, BRIP1,
MRE11A, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, RAD52, RAD54L,
or XRCC2, or any combination thereof. [0287] Item 38. The method
according to any one of items 35 to 37, wherein said cancer is
epithelial ovarian cancer, fallopian tube cancer, or primary
peritoneal cancer. [0288] Item 39. The crystalline niraparib
freebase of any one of items 1 to 28, or the composition of item 29
or 30, or the pharmaceutical composition of item 31, for use in a
method as defined in any one of items 34 to 38. [0289] Item 40. Use
of the crystalline niraparib freebase of any one of items 1 to 28,
or the composition of item 29 or 30, or the pharmaceutical
composition of item 31, in the manufacture of a medicament for use
in a method as defined in any one of items 34 to 38.
Examples
Analytical Procedures
X-Ray Power Diffraction
[0290] XRPD analysis was typically carried out on a PANalytical
X'pert pro, scanning the samples between 3 and 35.degree. 2.theta..
The material was gently ground to release any agglomerates and
loaded onto a multi-well plate with Kapton or Mylar polymer film to
support the sample. The multi-well plate was then placed into the
diffractometer and analysed using Cu K radiation (.mu..sub.1
.lamda.=1.54060 .ANG.; .alpha..sub.2=1.54443 .ANG.; .beta.=1.39225
.ANG.; .alpha..sub.1:.alpha..sub.2 ratio=0.5) running in
transmission mode (step size 0.0130.degree. 2.theta.) using 40
kV/40 mA generator settings.
Unless otherwise stated, the XRPD analysis was carried out at room
temperature and pressure and at a relative humidity of between
about 30 and about 50% (e.g. about 40%).
NMR Analysis
[0291] NMR methods were typically performed on a Bruker AVIIIHD
spectrometer equipped with a DCH cryoprobe. Experiments were
performed in deuterated DMSO and each sample was prepared to about
10 mM concentration. Unless otherwise stated, NMR spectra were
acquired at room temperature (e.g. around 300K).
High Performance Liquid Chromatography-Ultraviolet Detection
(HPLC-UV)
[0292] HPLC was typically performed using the following parameters:
[0293] Column: Waters Symmetry C18, 150.times.3.9 mm, 5 .mu.m
[0294] Column Temperature: 40.degree. C. [0295] Autosampler
Temperature: 5.degree. C. [0296] UV wavelength: 220 nm [0297]
Injection Volume: 4.3 .mu.L [0298] Flow Rate: 1.962 mL/mm [0299]
Mobile Phase A: 0.1% Perchloric acid in water [0300] Mobile Phase
B: Acetonitrile
[0301] The gradient program typically used was:
TABLE-US-00006 Time (minutes) Solvent B [%] 0 5 13.739 30 21.982 95
23.081 95 23.136 5 27.477 5
Gas Chromatography (GC)
[0302] CG analysis was typically performed on a Shimadzu GC2010
instrument, using a DB-624 column (30 m.times.0.32 mm, 1.8 .mu.m)
with a flame ionisation detector (240.degree. C.). The carrier gas
was nitrogen (30 mL/min) and hydrogen and air flow rates were 40
mL/min and 400 mL/min, respectively. An injection volume of 1.00
.mu.L was used and the column flow rate was 1.2 mL/min (linear
velocity). The program typically used was:
TABLE-US-00007 Injection temp. 200.degree. C. Hold at 45.degree. C.
5 minutes Ramp 10.degree. C./minute Hold at 220.degree. C. 5
minutes Run time: 25.5 min
Polarised Light Microscopy (PLM)
[0303] The presence of crystallinity (birefringence) was typically
determined using an Olympus BX50 polarising microscope, equipped
with a Motic camera and image capture software (Motic Images Plus
2.0). All images were recorded using the 20.times. objective,
unless otherwise stated.
Scanning Electron Microscopy (SEM)
[0304] SEM analysis was typically carried out using a Carl Zeiss
Sigma Field emission SEM. Samples were mounted onto stubs using
carbon tabs and coated with 15 nm AuPd and imaged at 5 KV, 30 .mu.m
aperture and 5 mm working distance.
Infrared Spectroscopy (FT-IR)
[0305] Infrared spectroscopy was typically carried out on a Bruker
ALPHA P spectrometer. Sufficient material was placed onto the
centre of the plate of the spectrometer and the spectra were
obtained using the following parameters: [0306] Resolution: 4 cm-1
[0307] Background Scan Time: 16 scans [0308] Sample Scan Time: 16
scans [0309] Data Collection: 4000 to 400 cm-1 [0310] Result
Spectrum: Transmittance [0311] Software: OPUS version 6
Thermogravimetric Analysis (TGA)
[0312] Typically, approximately 5 mg of material was weighed into
an open aluminium pan and loaded into a simultaneous
thermogravimetric/differential thermal analyser (TG/DTA) and held
at room temperature. The sample was then heated at a rate of
10.degree. C./min from 20.degree. C. to 350.degree. C. during which
time the change in sample weight was recorded along with any
differential thermal events (DTA). Nitrogen was used as the purge
gas, at a flow rate of 300 cm.sup.3/min.
Differential Scanning Calorimetry (DSC)
[0313] Typically, approximately 5 mg of material was weighed into
an aluminium DSC pan and sealed non-hermetically with a pierced
aluminium lid. The sample pan was then loaded into a Seiko DSC6200
(equipped with a cooler) cooled and held at 20.degree. C. Once a
stable heat-flow response was obtained, the sample and reference
were heated to melting (if possible) at a scan rate of 10.degree.
C./min and the resulting heat flow response monitored. Nitrogen was
used as the purge gas, at a flow rate of 50 cm.sup.3/min.
Variable Temperature X-Ray Powder Diffraction (VT-XRPD)
[0314] VT-XRPD analysis was typically carried out on a Philips
X'Pert Pro Multipurpose diffractometer equipped with a temperature
chamber. The samples were scanned between 4 and 35 .degree.2.theta.
using Cu K radiation (.alpha..sub.1 .lamda.=1.54060 .ANG.;
.alpha..sub.2=1.54443 .ANG.; .beta.=1.39225 .ANG.;
.alpha..sub.1:.alpha..sub.2 ratio=0.5) running in Bragg-Brentano
geometry (step size 0.008 .degree.2.theta.) using 40 kV/40 mA
generator settings. The program was as follows (unless otherwise
stated): [0315] Heat to 25.degree. C. at 10.degree.
C./min.fwdarw.5-minute hold.fwdarw.scan [0316] Heat to 200.degree.
C. at 10.degree. C./min.fwdarw.5-minute hold.fwdarw.scan [0317]
Cool to 25.degree. C. at -10.degree. C./min.fwdarw.5-minute
hold.fwdarw.scan [0318] Heat to 122.degree. C. at 10.degree.
C./min.fwdarw.5-minute hold.fwdarw.scan [0319] Heat to 132.degree.
C. at 10.degree. C./min.fwdarw.5-minute hold.fwdarw.scan [0320]
Heat to 150.degree. C. at 10.degree. C./min.fwdarw.5-minute
hold.fwdarw.scan [0321] Heat to 168.degree. C. at 10.degree.
C./min.fwdarw.5-minute hold.fwdarw.scan [0322] Heat to 171.degree.
C. at 10.degree. C./min.fwdarw.5-minute hold.fwdarw.scan [0323]
Heat to 200.degree. C. at 10.degree. C./min.fwdarw.5-minute
hold.fwdarw.scan [0324] Cool to 25.degree. C. at -10.degree.
C./min.fwdarw.5-minute hold.fwdarw.scan
Gravimetric Vapour Sorption (GVS)
[0325] Typically, approximately 10-20 mg of sample was placed into
a mesh vapour sorption balance pan and loaded into an IGASorp
Moisture Sorption Analyser balance by Hiden Analytical. The sample
was subjected to a ramping profile from 40-90% relative humidity
(RH) at 10% increments, maintaining the sample at each step until a
stable weight had been achieved (98% step completion, minimum step
length 30 minutes, maximum step length 60 minutes) at 25.degree. C.
After completion of the sorption cycle, the sample was dried using
the same procedure to 0% RH, and finally taken back to the starting
point of 40% RH. Two cycles were performed. The weight change
during the sorption/desorption cycles were plotted, allowing for
the hygroscopic nature of the sample to be determined.
Example 1: Crystalline Niraparib Freebase Form I
[0326] Niraparib freebase (Form I) was prepared by conversion of
niraparib tosylate monohydrate (obtained from niraparib e.g. as
described in WO 2014/088983 or PCT/US2018/029131) with sodium
hydroxide, followed by crystallization from 2-MeTHF.
Preparation of Niraparib Freebase (Form I)
[0327] To a mixture of 50.0 g (97.9 mmol) Niraparib tosylate
monohydrate in 2-MeTHF (1 L) was added 1% NaOH solution (500 mL) at
room temperature. After the mixture was stirred for 30 minutes, the
aqueous layer was separated and extracted with 2-MeTHF (0.5 L,
twice). The combined organic layer was washed with water (1 L). The
solution was concentrated under partial vacuum slowly below
30.degree. C. until about 20 ml of suspension was left. The mixture
was stirred for 30 minutes at room temperature and the solids were
collected by filtration, to give 23.8 g (75.9%) of off-white
crystalline solids (m.p. 189.degree. C.). [M+H].sup.+ at m/z 321,
with the expected isotope pattern. Purity was found to be
approximately 99.9% by HPLC.
[0328] .sup.1H NMR (500.12 MHz, DMSO-d6) .delta. 9.27 (s, 1H), 8.59
(dd, 1H, J=1.8, 4.7 Hz), 8.07 (dd, 1H, J=1.1, 7.0 Hz), 8.04 (d, 2H,
J=8.7 Hz), 8.02 (dd, 1H, J=1.1, 8.1 Hz), 7.90 (br. s, 1H), 7.46 (d,
2H, J=8.5 Hz), 7.27 (dd, 1H, J=7.2, 8.3 Hz), 3.00 (br. d, 1H,
J=12.1 Hz), 2.94 (br. d, 1H, J=12.1 Hz), 2.70 (m, 1H), 2.51 (m,
2H), 1.91, (d, 1H, J=13.0 Hz), 1.68 (m, 1H), 1.61 (m, 1H), 1.49 (m,
1H).
[0329] .sup.13C NMR (125.77 MHz, DMSO-d6) .delta. 166.1, 146.5,
146.4, 138.0, 130.1, 128.7 (2C), 125.8, 123.9, 123.8, 122.3, 121.9,
121.1 (2C), 54.0, 46.4, 43.6, 32.3 and 27.0.
Characterisation of Niraparib Freebase (Form I)
[0330] Niraparib freebase Form I was characterized by range of
analytical physical and chemical methods. The results indicated
that the Form I freebase is highly crystalline and
non-hygroscopic.
[0331] FIG. 1 shows the XRPD diffractogram of niraparib freebase
Form I. Table 1 below lists the diffraction angle values and
relative intensities:
TABLE-US-00008 TABLE 1 No. Pos. [.degree.2.theta.] d-spacing
[.ANG.] Rel. Int. [%] 1 8.3823 10.5486 3.44 2 12.1551 7.2816 7.50 3
12.8387 6.8954 0.79 4 13.6692 6.4783 1.46 5 15.5898 5.6842 19.09 6
16.4893 5.3761 24.96 7 16.9022 5.2457 26.73 8 17.4271 5.0889 6.63 9
18.0196 4.9229 2.44 10 18.7091 4.7430 100.00 11 19.5516 4.5405
36.68 12 20.0368 4.4316 7.27 13 21.6415 4.1065 27.68 14 22.3613
3.9759 23.09 15 22.5244 3.9475 38.04 16 23.2458 3.8266 20.73 17
24.4405 3.6422 1.99 18 25.0311 3.5576 5.67 19 25.2320 3.5297 8.51
20 25.6811 3.4690 6.09 21 27.3448 3.2616 2.34 22 27.9281 3.1948
8.00 23 29.3222 3.0460 12.72 24 30.4098 2.9395 1.75 25 30.9780
2.8868 2.80 26 31.9694 2.7995 1.92 27 32.7130 2.7376 1.07 28
33.2425 2.6952 3.38 29 33.8297 2.6497 3.21 30 34.7005 2.5852
2.09
[0332] Visible light spectroscopy (FIGS. 2A and 2B) indicated that
niraparib freebase Form I consisted of various aggregates of the
order of 10 .mu.m in size. The material appeared birefringent under
polarized light (FIGS. 2C and 2D).
[0333] FIG. 3 shows SEM analysis of niraparib freebase Form I at
various scales.
[0334] FIG. 4 shows the FT-IR spectrum of niraparib freebase Form
I. Table 2 below lists the diffraction angles:
TABLE-US-00009 TABLE 2 Wavenumber [cm.sup.1] Transmittance [%]
3362.78 81.9% 3115.66 86.3% 3059.06 85.3% 2933.38 81.4% 2914.63
82.8% 2849.12 86.7% 2806.63 83.5% 2731.73 87.9% 1650.29 72.5%
1608.16 85.1% 1555.35 87.2% 1523.69 74.7% 1465.87 88.8% 1424.75
85.4% 1398.79 83.9% 1363.90 69.5% 1322.05 81.4% 1297.99 80.8%
1280.34 86.6% 1280.34 86.6% 1255.04 87.3% 1204.54 82.9% 1154.15
91.1% 1133.94 89.8% 1114.29 87.1% 1087.48 93.0% 1047.29 85.3%
1008.42 86.0% 960.40 88.4% 929.83 96.2% 884.37 93.6% 854.04 81.1%
837.22 79.0% 818.54 77.4% 782.79 81.2% 770.43 75.4% 749.64 67.5%
730.11 78.6% 629.94 74.7% 609.29 72.9% 557.63 76.5% 518.39 67.5%
480.68 87.6% 463.48 91.5% 451.85 88.9% 413.43 95.6% 413.43
95.6%
[0335] The major absorption bands are consistent with the
structure, whereby peaks at 3373-2807 cm.sup.-1 are assigned as
N--H and C--H stretches (amide, NH.sub.2 and alkane/alkene), the
peak at 1652 is assigned as the C.dbd.O stretch (amide), and the
band at 1608 is assigned as the N--H bend (amide).
[0336] FIG. 5 shows the Raman spectrum of niraparib freebase
(.lamda..sub.ex=785 nm). Table 3 below lists the peaks:
TABLE-US-00010 TABLE 3 Raman Shift (cm.sup.-1) Intensity 110.45
6.56E+04 254.98 1.35E+04 283.46 1.70E+04 359.14 1.35E+04 376.96
1.26E+04 411.15 1.87E+04 467.70 1.35E+04 481.44 1.25E+04 518.73
1.15E+04 536.05 1.18E+04 558.24 1.15E+04 587.69 1.45E+04 627.94
1.56E+04 635.22 1.73E+04 670.30 1.39E+04 718.33 1.49E+04 737.42
1.32E+04 767.13 1.26E+04 795.49 1.41E+04 819.01 1.11E+04 834.25
1.07E+04 851.78 1.06E+04 869.25 1.33E+04 892.46 9.12E+03 932.83
9.90E+03 960.34 1.01E+05 1009.29 2.30E+04 1052.17 2.01E+04 1086.89
8.91E+03 1135.79 1.13E+04 1155.67 1.18E+04 1197.38 3.30E+04 1252.85
1.73E+04 1280.90 1.20E+04 1300.23 1.53E+04 1352.48 1.75E+04 1382.11
4.13E+04 1457.50 1.02E+05 1527.70 4.63E+04 1556.32 2.65E+04 1607.01
6.79E+04
[0337] A TG thermogram is presented in FIG. 6 (top line, right-hand
axis), which shows no significant loss in mass from the outset. The
DTA thermogram (FIG. 6, diagonal line, left-hand axis) shows a
sharp endothermic event (.DELTA.H=96.2 J/g) which is likely due to
the melt of the material with an onset of approximately 188.degree.
C.
[0338] The DSC thermogram is presented in FIG. 7, which shows a
single sharp endothermic event (onset .about.189.0.degree. C.),
likely due to the sample melting.
[0339] The GVS isotherm (double cycle) is presented in FIG. 8. The
GVS analysis shows about 0.7% mass increase up to 90% RH. Hence,
the material is non-hydroscopic.
[0340] Karl Fischer titration determined the water content as being
0.29% (average of two experiments).
Example 2: Amorphous Niraparib Freebase
[0341] Amorphous
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide may be
prepared, for example, in accordance with the synthetic scheme
described in Jones et al. (J. Med. Chem., 2009, 52:7170-7185). In
brief, the title compound is prepared by separation of racemic
3-{4-[7-(aminocarbonyl)-2H-indazol-2-yl]phenyl}piperidinium
chloride by chiral SFC purification using CO.sub.2 as supercritical
eluent (column, Chiralpak AS-H, 1 mm.times.25 mm; flow=10 mL/min;
T.sub.col=35.degree. C.; P.sub.col=100 bar; modifier, 55% PrOH
containing 4% Et.sub.2NH).
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide elutes
as a second peak (RT=6.51 min) and evaporation of the solvent
followed by lyophilization gives the title compound as a white
powder (99.2% ee).
[0342] Alternatively, the title compound may be prepared by
lyophilisation of a solution prepared by dissolving one of the
crystalline forms of niraparib disclosed herein, e.g. Form I as
described in Example 1. In brief, 140 mg of niraparib freebase form
I was dissolved (with gentle heating) in 1,4-dioxane (.about.10 mL)
and water (.about.8 mL) and split equally into 14 vials. These
vials were then frozen at -50.degree. C., before freeze drying
overnight. One vial of lyophilized material was taken for analysis
by XRPD.
[0343] FIG. 9 shows the XRPD diffractogram of amorphous niraparib
freebase prepared by lyophilisation, from which it may be observed
that the material is substantially in amorphous form.
Example 3: Crystalline Niraparib Freebase Form II and Form III
[0344] Crystalline niraparib freebase was obtained in crystalline
form from solution/suspension in ethanol (Form II) and in MEK,
2-propanol, acetone, TBME, THF and toluene (Form III).
[0345] In brief, 50 .mu.L aliquots of the appropriate solvent were
added sequentially to vials of amorphous niraparib freebase
(obtained as described in Example 2). Between each addition, the
mixture was checked for dissolution and, if no dissolution was
apparent, the mixture was heated to about 50.degree. C. and checked
again. After 300 .mu.L of solvent had been added, 100 .mu.L
aliquots were added sequentially. This procedure was continued
until dissolution was observed or until 1 mL of solvent had been
added. If no dissolution occurred, the solids were isolated by
filtration and an XRPD pattern was collected. If dissolution
occurred, the solvent was evaporated and an XRPD pattern was
collected on any solid which remained. Complete dissolution was
observed only in ethanol (with heating to about 40.degree. C.).
Niraparib freebase was partially soluble in 2-propanol.
[0346] XRPD diffractograms for niraparib freebase Form II (from
ethanol) and Form III (from acetone) are shown in FIGS. 10 and 11,
respectively. Tables 4 and 5 below list the diffraction angle
values and relative intensities from FIGS. 10 and 11,
respectively:
TABLE-US-00011 TABLE 4 No. Pos. [.degree.2.theta.] d-spacing
[.ANG.] Rel. Int. [%] 1 3.2491 27.19352 1.88 2 8.6308 10.24539
28.68 3 17.2713 5.13442 100 4 20.0921 4.41951 10.68 5 21.2796
4.17549 10.52 6 21.5672 4.12045 29.82 7 21.6942 4.09662 65.81 8
21.8277 4.07186 52.02 9 22.5690 3.93977 12.7 10 23.9505 3.71555
8.23 11 25.8225 3.45028 48.68 12 26.3938 3.37689 28.57 13 28.4803
3.13406 3.93 14 31.7522 2.81819 3.92
TABLE-US-00012 TABLE 5 No. Pos. [.degree.2.theta.] d-spacing
[.ANG.] Rel. Int. [%] 1 8.6651 10.2050 2.88 2 10.1464 8.71817 3.83
3 11.9103 7.43071 2.02 4 13.6013 6.51043 42.66 5 13.8199 6.40797
12.96 6 14.5644 6.08204 5.33 7 15.8975 5.57490 4.32 8 17.3461
5.11246 100 9 19.6712 4.51310 4.9 10 20.5305 4.32612 53.06 11
21.2584 4.1796 24.86 12 21.6632 4.10241 18.6 13 22.2805 3.99013
15.23 14 23.7043 3.75358 10.81 15 24.1170 3.69027 11
Example 4: Crystalline Niraparib Freebase Form IV
[0347] Niraparib freebase Form IV was obtained using a melt-cooling
cycle.
[0348] 5 mg of niraparib freebase Form I was weighed into an
aluminum DSC pan and sealed non-hermetically with a pierced
aluminum lid. The sample pan was then loaded into a Seiko DSC6200
(equipped with a cooler) cooled and held at 20.degree. C. Once a
stable heat-flow response was obtained, the sample and reference
were heated to melting at a scan rate of 10.degree. C./min and the
resulting heat flow response monitored. Nitrogen was used as the
purge gas, at a flow rate of 50 cm.sup.3/min. The material was
heated to just beyond melting (about 200.degree. C.) before being
cooled to 20.degree. C. and then heated to melting again.
[0349] After the first melt and cool cycle, the DSC thermogram
(shown in FIG. 12) was different to the thermogram for Form I, and
it exhibited an exothermic event (onset about 122.degree. C.) which
was possibly due to recrystallisation. When assessed using VT-XRPD
with the same heat profile, the XRPD pattern indicated that
amorphous material was obtained after the first melt-cool cycle
(FIG. 13). When reheated to about 122.degree. C., the XRPD pattern
indicated recrystallization to Form IV which persisted until the
onset of melting at about 168.degree. C. when a further
recrystallization occurred (FIG. 14). Table 6 below lists the
diffraction angle values and relative intensities from the XRPD
diffractogram of niraparib freebase Form IV (FIG. 14, 122.degree.
C. trace):
TABLE-US-00013 TABLE 6 No. Pos. [.degree.2.theta.] d-spacing
[.ANG.] Rel. Int. [%] 1 7.2897 12.12706 7.23 2 12.8787 6.87406
12.09 3 13.7214 6.45372 7.49 4 14.4157 6.14445 31.13 5 15.3722
5.76422 7.37 6 17.0799 5.19152 24.88 7 17.3449 5.11281 29.45 8
17.5681 5.04836 21.77 9 18.9128 4.69234 54.7 10 19.2787 4.60411
20.54 11 19.6560 4.51656 35.3 12 19.8048 4.48295 24.17 13 20.1189
4.41369 73.67 14 20.9821 4.23401 15.13 15 21.8744 4.06327 100 16
22.0906 4.02399 45.2 17 22.5105 3.94988 9.93 18 24.0719 3.69708
8.66 19 24.8577 3.58198 7.52 20 27.6580 3.22534 13.03
[0350] The .sup.1H-NMR spectra of Form IV (FIG. 16, lower trace)
was identical to that of Form I (FIG. 16, upper trace), which
indicates that no chemical reaction occurred during the reheating
process but that some structural changes took place.
Example 5: Solubility Studies on Niraparib Freebase
[0351] The aqueous solubility of niraparib freebase (Form I and
amorphous) was assessed under conditions of varying
(physiologically relevant) pH.
[0352] For each sample, 30 mg of the freebase was weighed into
vials (in triplicate) and 1 mL of water or buffer was added. The
following buffers (50 mM in each case) used were: [0353] pH 1 25 mL
KCl solution (1.49 g dissolved in 100 mL water) and 42.5 mL HCl
solution (1.66 mL made up to 100 mL with water) were added together
and made up to 100 mL with water; [0354] pH 4.5 anhydrous sodium
acetate (1.07 g) was dissolved in water (about 150 mL) before
adding 5.9 mL acetic acid solution (11.6 mL glacial acetic acid
made up to 100 mL with water). The resulting solution was made up
to 500 mL with water; and [0355] pH 6.8 25 mL of KH.sub.2PO.sub.4
solution (2.72 g dissolved in about 80 mL water and made up to 100
mL with water) and 11.2 mL of NaOH solution (800 mg of sodium
hydroxide was dissolved and diluted to 100 mL with water) were
added together and made up to 100 mL with water.
[0356] The resulting samples were shaken at 37.degree. C. for 1
hour. A further 20 mg of crystalline freebase was added to the pH 1
buffer sample. All samples were then shaken at 37.degree. C. for 23
hours. Each sample was then filtered and the concentration of
niraparib in the mother liquor was assessed by HPLC. Any solids
which were isolated by filtration were assessed by XRPD to
determine whether the form of the material had changed.
[0357] The solubility of amorphous niraparib freebase and niraparib
freebase Form I is shown in Table 7 below. In each case, the
solubility value reported is the average of the triplicate
measurements on the concentration of niraparib in solution.
TABLE-US-00014 TABLE 7 Solubility of Solubility of Amorphous Form
Crystalline Form I Buffer (mg/mL) (mg/mL) pH 1 11.8 30.9 pH 4.5
13.4 11.8 pH 6.8 0.6 0.7 water 0.8 <0.1
[0358] The data in Table 7 suggest that crystalline niraparib
freebase has a solubility in low pH media which is as good as (if
not better than) the amorphous form of the compound. This suggests
potential advantages for administration of the compound in vivo,
e.g. in the low pH environment of the stomach.
[0359] The XRPD data obtained on the solid material which remained
after filtration of the crystalline samples indicated that the
crystalline form was unchanged in each case. The XRPD data obtained
on the solid material which remained after filtration of the
amorphous samples suggested that a new crystalline form was
obtained (Form V). An exemplary XRPD spectrum (from the sample
which was shaken with water) is shown in FIG. 15. Table 8 below
lists the diffraction angle values and relative intensities from
the XRPD diffractogram of FIG. 15:
TABLE-US-00015 TABLE 8 No. Pos. [.degree.2.theta.] d-spacing
[.ANG.] Rel. Int. [%] 1 5.9009 14.97771 46.64 2 8.0477 10.98642
9.63 3 9.7155 9.10387 14.55 4 12.1093 7.30906 11.38 5 14.4475
6.13099 28.04 6 14.8307 5.97341 21.42 7 15.1139 5.86210 14.63 8
15.8408 5.59473 19.62 9 16.7162 5.30367 20.47 10 19.4925 4.55407
16.75 11 20.8047 4.26972 100 12 21.3110 4.16941 34.33 13 21.6446
4.10589 57.39 14 22.7189 3.91411 14.43 15 23.0141 3.86457 12.23 16
24.3453 3.65618 13 17 26.5471 3.35774 8.7 18 27.2877 3.26826 8.72
19 28.5177 3.13003 9.88 20 29.1926 3.05919 15.93
[0360] The teachings of all patents, published applications and
references cited herein are incorporated by reference in their
entirety.
[0361] While the present invention has particularly been shown and
described with reference to exemplary embodiments thereof, it will
be understood by those skilled in the art that various changes in
form and details may be made therein without departing from the
sprit and scope of the invention encompassed by the appended
claims.
* * * * *