Note: Descriptions are shown in the official language in which they were submitted.
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CRYSTALLINE SALT OF A TRICYCLIC POLY(ADP-
RIBOSE) POLYMERASE INHIBITOR
FIELD OF THE INVENTION
The present invention relates to crystalline rucaparib mesylate salt and to a
process for its
preparation. Furthermore, the invention relates to a pharmaceutical
composition comprising the
crystalline rucaparib mesylate salt and at least one pharmaceutically
acceptable excipient. The
pharmaceutical composition of the present invention can be used as a
medicament, in particular
for the treatment of cancer.
BACKGROUND OF THE INVENTION
Rucaparib is an oral, small molecule inhibitor of poly(ADP-ribose) polymerase
(PARP)
enzymes including PARP-1, PARP-2 and PARP-3, which play a role in DNA repair.
PARP
inhibitors have been described to be useful as therapeutics in treatment of
cancers and in the
amelioration of the effects of stroke, head trauma and neurodegenerative
disease. Chemically
designated as 8 -fluoro-2- (4-methylaminomethyl-pheny1)- 1,3 ,4,5-tetrahydro-
azepino [5,4,3-
cd]indol-6-one, rucaparib may be represented by the chemical structure as
depicted in formula
I:
o
F
0 NH
HN /
41
/
NH
formula (I)
Rucaparib is approved in the USA as a monotherapy for the treatment of
patients with the
BRCA mutation (germline and/or somatic), the mutation occuring in patients
with advanced
ovarian cancer who have been previously treated with two or more
chemotherapeutic regimens.
The active ingredient in the commercial product (Rubraca ) is the camsylate
salt of rucaparib.
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WO 00/42040 Al discloses tricyclic PARP inhibiting agents and pharmaceutically
acceptable
salts thereof. One of said PARP inhibitors is rucaparib, which was synthesized
as the free base
with a melting point of 154-155 C in example IIII of said application.
Various salts of rucaparib and different solid state modifications thereof are
disclosed in
applications WO 2004/087713 Al, WO 2006/033007 A2 and WO 2011/098971 Al.
WO 2004/087713 Al for instance discloses in example A the preparation of the
mesylate salt
of rucaparib, which was prepared by treating rucaparib free base with methane
sulfonic acid in
the presence of methanol. After partial concentration of the methanol solution
in vacuo, water
was added followed by lyophilization, which yielded rucaparib mesylate as
bright yellow solid.
The molecular formula provided in example A indicates that the obtained
rucaparib mesylate
contains about 2 mol equivalents of water per mol rucaparib mesylate. The
aqueous solubility
of the prepared rucaparib mesylate was determined to be 15.5 mg/mL (see table
"water
solubilities of different salt forms", page 8 of WO 2004/087713 Al).
Different solid form modifications of a compound can possess different
physicochemical
properties such as but not limited to melting point, physical and chemical
stability,
hygroscopicity, solubility, flowability, wettability and compressibility. Most
drug products are
administered as oral solid dosage forms, but not every solid form modification
of a compound
is suitable for being formulated e.g. as a tablet or capsule, because some
have unfavorable
physicochemical properties. For example, the rucaparib mesylate salt disclosed
in WO
2004/087713 Al has a significant water content and shows only limited water
solubility, both
properties not being ideal for the formulation of pharmaceutical drug
products.
It is thus an objective of the present invention to provide an improved
rucaparib mesylate salt
form, e.g. a form of rucaparib mesylate which has a low water content, is non-
hygroscopic,
shows increased aqueous solubility and/or which is chemically and physically
stable.
SUMMARY OF THE INVENTION
The invention solves one or more of the above defined problems by providing
crystalline
rucaparib mesylate in anhydrous form. The crystalline rucaparib mesylate of
the present
invention possesses one or more improved physicochemical properties selected
from solubility,
dissolution rate, hygroscopicity, chemical stability, physical stability,
morphology, flowability,
bulk density and compressibility. In particular, the crystalline rucaparib
mesylate of the present
invention is non-hygroscopic and physically stable upon moisture contact. In
addition, it was
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found that the crystalline rucaparib mesylate of the present invention shows
increased water
solubility and requires fewer production steps compared to the mesylate salt
disclosed in WO
2004/087713 Al.
Definitions
The term "rucaparib" as used herein refers to the compound with the chemical
name 8-fluoro-
2-(4-methylaminomethyl-pheny1)-1,3,4,5-tetrahydro-azepino[5,4,3-cd] indo1-6-
one, which is
represented by the chemical structure as depicted in formula I above. The term
"rucaparib"
indicates the free base form.
As used herein the term "room temperature" refers to a temperature in the
range of from 20 to
30 C.
As used herein, the term "measured at a temperature in the range of from 20 to
30 C" refers to
a measurement under standard conditions. Typically, standard conditions mean a
temperature
in the range of from 20 to 30 C, i.e. at room temperature. Standard
conditions can mean a
temperature of about 22 C. Typically, standard conditions can additionally
mean a
measurement under 20-75% relative humidity, preferably 30-70% relative
humidity, more
preferably 40-60% relative humidity and most preferably 50% relative humidity.
The term "reflection" with regards to powder X-ray diffraction as used herein,
means peaks in
an X-ray diffractogram, which are caused at certain diffraction angles (Bragg
angles) by
constructive interference from X-rays scattered by parallel planes of atoms in
solid material,
which are distributed in an ordered and repetitive pattern in a long-range
positional order. Such
a solid material is classified as crystalline material, whereas amorphous
material is defined as
solid material, which lacks long-range order and only displays short-range
order, thus resulting
in broad scattering. Hence, amorphous material does not display a definitive X-
ray diffraction
pattern with reflections. According to literature, long-range order e.g.
extends over at least 103
atoms, whereas short-range order is over a few atoms only (see "Fundamentals
of Powder
Diffraction and Structural Characterization of Materials" by Vitalij K.
Pecharsky and Peter Y.
Zavalij, Kluwer Academic Publishers, 2003, page 3).
The term "essentially the same" with reference to powder X-ray diffraction
means that
variabilities in reflection positions and relative intensities of the
reflections are to be taken into
account. For example, a typical precision of the 2-Theta values is in the
range of 0.2 2-Theta.
Thus, a reflection that usually appears at 22.5 2-Theta for example can
appear between 22.3
and 22.7 2-Theta on most X-ray diffractometers under standard conditions.
Furthermore, one
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skilled in the art will appreciate that relative intensities of the
reflections will show inter-
apparatus variability as well as variability due to degree of crystallinity,
preferred orientation,
sample preparation and other factors known to those skilled in the art and
should be taken as
qualitative measure only.
The crystalline rucaparib mesylate of the present invention may be referred to
herein as being
characterized by graphical data "as shown in" a figure. Such data include for
example powder
X-ray diffractograms. The person skilled in the art understands that factors
such as variations
in instrument type, response and variations in sample directionality, sample
concentration and
sample purity may lead to small variations for such data when presented in
graphical form, for
example variations relating to the exact peak positions and intensities.
The term "solid form", "solid form modification" or "physical form" as used
herein refers to
any crystalline or amorphous phase of a substance.
The terms "anhydrous" or "anhydrate" as used herein refer to a crystalline
solid where no water
is incorporated in or accommodated by the crystal structure. Anhydrous forms
may still contain
residual water, which is not part of the crystal structure but may be adsorbed
on the surface or
absorbed in disordered regions of the crystal. Typically, an anhydrous form
does not contain
more than 2.0 weight%, preferably not more than 1.5 weight% and most
preferably not more
than 1.0 weight% of water, based on the weight of the crystalline form. The
water content is to
be determined by Karl-Fischer Coulometry of a sample that has been
equilibrated with an
atmosphere of 25 C and 40% relative humidity.
The term "non-hygroscopic" as used herein refers to a compound which shows a
water uptake
of at most 2.0 weight-%, preferably of at most 1.5 weight-%, such as at most
1.0 weight %, in
the sorption cycle when measured with gravimetric moisture sorption at a
relative humidity in
the range of from 0 to 90% and a temperature of 25.0 0.1 C, based on the
weight of the
compound.
The term "non-solvated" as used herein, when talking about a crystalline solid
indicates that no
organic solvent is incorporated in or accommodated by the crystal structure.
Non-solvated
forms may still contain residual organic solvents, which are not part of the
crystal structure but
may be adsorbed on the surface or absorbed in disordered regions of the
crystal. Typically, a
non-solvated form does not contain more than 1.0 weight%, preferably not more
than 0.5
weight%, and most preferably not more than 0.3 weight%, 0.2 weight% or 0.1
weight% of
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organic solvents, based on the weight of the crystalline form. The organic
solvent content can
be determined by 1H-NMR.
A "predetermined amount" as used herein with regard to the crystalline
rucaparib mesylate of
the present invention refers to the initial amount of the crystalline
rucaparib mesylate of the
5 present invention used for the preparation of a pharmaceutical
composition having a desired
dosage strength of rucaparib.
The term "effective amount" as used herein with regard to the crystalline
rucaparib mesylate of
the present invention encompasses an amount of the crystalline rucaparib
mesylate of the
present invention, which provides the desired therapeutic and/or prophylactic
effect.
The term "pharmaceutically acceptable excipient" as used herein refers to
substances, which do
not show a significant pharmacological activity at the given dose and that are
added to a
pharmaceutical composition in addition to the active pharmaceutical
ingredient. Excipients may
take on the function of vehicle, diluent, release agent, disintegrating agent,
dissolution
modifying agent, absorption enhancer, stabilizer or a manufacturing aid among
others.
Excipients may include fillers (diluents), binders, disintegrants, lubricants
and glidants.
The terms "filler" or "diluent" as used herein refer to substances that are
used to dilute the active
pharmaceutical ingredient prior to delivery. Diluents and fillers can also
serve as stabilizers.
As used herein the term "binder" refers to substances which bind the active
pharmaceutical
ingredient and pharmaceutically acceptable excipient together to maintain
cohesive and discrete
portions.
The terms "disintegrant" or "disintegrating agent" as used herein refers to
substances which,
upon addition to a solid pharmaceutical composition, facilitate its break-up
or disintegration
after administration and permits the release of the active pharmaceutical
ingredient as
efficiently as possible to allow for its rapid dissolution.
The term "lubricant" as used herein refers to substances which are added to a
powder blend to
prevent the compacted powder mass from sticking to the equipment during
tableting or
encapsulation process. They aid the ejection of the tablet from the dies and
can improve powder
flow.
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The term "glidant" as used herein refers to substances which are used for
tablet and capsule
formulations in order to improve flow properties during tablet compression and
to produce an
anti-caking effect.
As used herein, the term "about" means within a statistically meaningful range
of a value. Such
a range can be within an order of magnitude, typically within 10%, more
typically within 5%,
even more typically within 1% and most typically within 0.1% of the indicated
value or range.
Sometimes, such a range can lie within the experimental error, typical of
standard methods used
for the measurement and/or determination of a given value or range.
As used herein, the term "mother liquor" refers to the solution remaining
after crystallization
of a solid.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: illustrates a representative powder X-ray diffractogram of the
crystalline form of
rucaparib mesylate (form A) according to the present invention. The x-axis
shows the scattering
angle in 2-Theta, the y-axis shows the intensity of the scattered X-ray beam
in counts of
detected photons.
Figure 2: illustrates a representative differential scanning calorimetry curve
of the crystalline
form of rucaparib mesylate (form A) according to the present invention. The x-
axis shows the
temperature in degree Celsius ( C), the y-axis shows the heat flow in Joule
per gram (J/g) with
endothermic peaks going up.
Figure 3: illustrates gravimetric moisture sorption and desorption curves of
the crystalline form
of rucaparib mesylate (form A) of the present invention. The x-axis shows the
relative humidity
the y-axis shows the mass change each in percent (%).
Figure 4: illustrates a powder X-ray diffractogram of a composition comprising
the crystalline
form of rucaparib mesylate (form A) according to the present invention. The x-
axis shows the
scattering angle in 2-Theta, the y-axis shows the intensity of the scattered
X-ray beam in counts
of detected photons.
DETAILED DESCRIPTION OF THE INVENTION
The present inventors have surprisingly found that anhydrous crystalline
rucaparib mesylate of
the present invention posseses advantageous physicochemical properties making
it particularly
useful for the preparation of a pharmaceutical drug product. While the
rucaparib mesylate salt
of WO 2004/087713 Al has certain drawbacks associated with its usability for
the preparation
of solid dosage forms such as significant water content and limited aqueous
solubility, the
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crystalline meslyate salt form of the present invention, hereinafter also
designated as form A,
was found to be non-hygroscopic and physically stable upon moisture stress. In
addition, it was
found that the crystalline rucaparib mesylate of the present invention shows
increased water
solubility compared to the mesylate salt disclosed in WO 2004/087713 Al. The
latter property
may not only translate into higher bioavailability for oral drug products but
also allow for the
preparation of more customized liquid formulations. Besides, the crystalline
rucaparib mesylate
form of the present invention can be prepared in fewer steps than the mesylate
salt of WO
2004/087713 Al. A shorter process, with controlled crystallization conditions,
is advantageous
for the production of rucaparib mesylate, for example with regard to quality
and overall cost.
Different aspects of the invention are described below in further detail by
embodiments, without
being limited thereto. Each aspect of the invention may be described by one
embodiment or by
combining two or more of the embodiments.
In a first aspect, the present invention relates to anhydrous crystalline
rucaparib mesylate.
More preferably, the anhydrous crystalline rucaparib mesylate of the present
invention is
characterized by the chemical structure according to formula (II)
0
F0 NH
HN /
111
/S'CH3
/
NH2+
formula (II).
Preferably, the anhydrous crystalline rucaparib mesylate of the present
invention as defined in
any one of the embodiments described above is characterized by a molar ratio
of rucaparib and
methanesulfonic acid in the range of from 1.0: 0.8 to 1.0: 1.2, preferably of
from 1.0: 0.9 to 1.0:
1.1 and most preferably the molar ratio is about 1.0: 1Ø
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The anhydrous crystalline rucaparib mesylate of the present invention may be
characterized by
analytical methods well known in the field of the pharmaceutical industry for
characterizing
solids. Such methods comprise but are not limited to powder X-ray diffraction,
differential
scanning calorimetry, thermogravimetric analysis and gravimetric moisture
sorption. It may be
characterized by one of the aforementioned analytical methods or by combining
two or more
of them. In particular, the anhydrous crystalline rucaparib mesylate of the
present invention
may be characterized by any one of the following embodiments or by combining
two or more
of the following embodiments.
Hence, in one embodiment the present invention relates to anhydrous
crystalline rucaparib
mesylate (form A) characterized by having a powder X-ray diffractogram
comprising
reflections at 2-Theta angles of:
(9.9 0.2) , (12.2 0.2) and (22.5 0.2) ;
(9.9 0.2) , (11.7 0.2) , (12.2 0.2) and (22.5 0.2) ;
(9.9 0.2) , (11.7 0.2) , (12.2 0.2) , (16.3 0.2) and (22.5 0.2) ;
(9.9 0.2) , (11.7 0.2) , (12.2 0.2) , (16.3 0.2) , (17.7 0.2) and
(22.5 0.2) ;
(9.9 0.2) , (11.7 0.2) , (12.2 0.2) , (16.3 0.2) , (17.7 0.2) ,
(20.7 0.2) and (22.5
0.2) ;
(9.9 0.2) , (11.7 0.2) , (12.2 0.2) , (15.0 0.2) , (16.3 0.2) ,
(17.7 0.2) , (20.7 0.2)
and (22.5 0.2) ;
(9.9 0.2) , (11.7 0.2) , (12.2 0.2) , (15.0 0.2) , (16.3 0.2) ,
(17.7 0.2) (19.8 0.2) ,
(20.7 0.2) and (22.5 0.2) ;
(9.9 0.2) , (11.7 0.2) , (12.2 0.2) , (13.9 0.2) , (15.0 0.2) ,
(16.3 0.2) , (17.7 0.2)
(19.8 0.2) , (20.7 0.2) and (22.5 0.2) ;
when measured at a temperature in the range of from 20 to 30 C with Cu-Kalpha
radiation
having a wavelength of 0.15419 nm.
In another embodiment, the present invention relates to anhydrous crystalline
rucaparib
mesylate (form A) characterized by having a powder X-ray diffractogram
essentially the same
as shown in figure 1 of the present invention, when measured at a temperature
in the range of
from 20 to 30 C with Cu-Kalpha radiation having a wavelength of 0.15419 nm.
In a further embodiment, the present invention relates to anhydrous
crystalline rucaparib
mesylate (form A) characterized by having a differential scanning calorimetry
curve showing
an endothermic peak, preferably a sole endothermic peak in the range of from
290 to 300 C,
preferably from 294 to 297 C, when measured at a heating rate of 10 K/min.
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In yet a further embodiment, the present invention relates to anhydrous
crystalline rucaparib
mesylate (form A) characterized by having a differential scanning calorimetry
curve showing
an endothermic peak, preferably a sole endothermic peak with an onset
temperature in the range
of from 290 to 298 C, preferably of from 292 to 296 C, for example with an
onset temperature
of about 294 C, when measured at a heating rate of 10 K/min.
In still a further embodiment, the present invention relates to anhydrous
crystalline rucaparib
mesylate (form A) characterized by having a differential scanning calorimetry
curve showing
an endothermic peak, preferably a sole endothermic peak with a peak
temperature in the range
of from 294 to 300 C, preferably of from 296 to 298 C, for example with an
onset temperature
of about 297 C, when measured at a heating rate of 10 K/min.
Preferably, the endothermic peak, more preferably the sole endothermic peak is
caused by the
melting of the anhydrous crystalline rucaparib mesylate (form A) of the
present invention.
In another embodiment, the present invention relates to anhydrous crystalline
rucaparib
mesylate (form A) characterized by having a thermogravimetric analysis curve
showing a mass
loss of not more than 1.0 weight-%, preferably of not more than 0.8 weight-%,
based on the
weight of the crystalline form, when measured from 25 to 250 C at a heating
rate of 10 K/min.
In a particular preferred embodiment, the present invention relates to
anhydrous crystalline
rucaparib mesylate as defined in any one of the above described embodiments,
which is non-
solvated.
In yet another embodiment, the present invention relates to anhydrous non-
hygroscopic
crystalline rucaparib mesylate (form A), characterized by having a water
content of less than
1.0 weight-%, preferably less than 0.9 weight-%, based on the weight of the
crystalline form,
when measured at 25 C at a relative humidity in the range of from 0 to 90%,
preferably of
from 1 to 90%, even more preferably of from 10 to 90%.
In another aspect the invention relates to a composition comprising at least
90 weight-%,
preferably at least 95 weight-% of the anhydrous crystalline rucaparib
mesylate (form A) as
defined in any one of the above described embodiments, based on the total
weight of the
composition.
In a preferred embodiment, the invention relates to a composition comprising
at least 90 weight-
%, preferably at least 95 weight-% of the anhydrous crystalline rucaparib
mesylate (form A) as
defined in any one of the above described embodiments characterized by a
powder X-ray
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diffractogram comprising reflections at 2-Theta angles selected from the group
consisting of
(9.9 0.2) , (12.2 0.2) and/or (22.5 0.2) , when measured at a
temperature in the range of
from 20 to 30 C with Cu-Kalpha radiation having a wavelength of 0.15419 nm.
It was surprisingly found by the present inventors that the anhydrous
crystalline mesylate salt
5 of the present invention possesses advantageous properties compared to
the mesylate salt of
WO 2004/087713 Al, which render the anhydrous crystalline mesylate salt of the
present
invention especially suitable for the formulation of safe and efficacious drug
products. For
example, the anhydrous crystalline meslyate salt of the present invention is
non-hygroscopic
and shows a reversible water uptake of less than 0.9 weight-% in the range of
from 0 to 90%
10 relative humidity. The powder X-ray diffractograms before and after
gravimetric moisture
sorption do not show any significant differences, indicating that the
anhydrous crystalline
rucaparib mesylate is physically stable under moisture stress. In contrast,
the molecular formula
of the rucaparib mesylate salt provided in example A of WO 2004/087713 Al
indicates that the
obtained rucaparib mesylate contains about 2 mol equivalents of water.
In addition, it was found that the anhydrous crystalline rucaparib mesylate of
the present
invention shows increased water solubility (> 18 g/L, see example 1) compared
to the mesylate
salt disclosed in WO 2004/087713 Al (15.5 mg/mL, see table "water solubilities
of different
salt forms", page 8 of WO 2004/087713 Al). The latter property may not only
translate into
higher bioavailability for oral drug products but also allow for the
preparation of more
customized liquid formulations.
Also from a process perspective, the anhydrous crystalline rucaparib mesylate
of the present
invention possesses favorable characteristics over the mesylate salt of WO
2004/087713 Al. It
can be prepared by a simple controlled crystallization process from a solvent
which is attractive
from an economic point of view. In contrast, the process provided in example A
of WO
.. 2004/087713 Al involves a solvent exchange from methanol to water after the
salt formation,
followed by lyophilization.
Hence, in a further aspect, the invention relates to a process for the
preparation of the anhydrous
crystalline rucaparib mesylate as defined in any one of the embodiments
described above or the
composition comprising the same as defined in any one of the embodiments
described above
comprising:
(i) reacting rucaparib with methane sulfonic acid in the presence of a
suitable
solvent or solvent mixture;
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(ii) crystallizing rucaparib mesylate from the mixture provided in step (i);
(iii) optionally separating at least a part of the crystals obtained in step
(ii) from the
mother liquor;
(iv) optionally drying the crystals obtained in any one of previous steps (i)
or (ii);
(v) optionally equilibrating the crystals obtained in any one of previous
steps (i) to
(iii) with an atmosphere having a temperature of 40 C and a relative humidity
of 75%.
The rucaparib free base starting material of step (i) above may be prepared
according to the
process provided in example IIII of WO 00/42040 Al. A suitable solvent or
solvent mixture in
step (i) of the process for the preparation of the anhydrous crystalline
rucaparib mesylate of the
present invention is selected from acetone, tetrahydrofuran or a mixture
thereof. Rucaparib is
treated with methane sulfonic acid in the presence of a suitable solvent or
solvent mixture,
wherein the molar ratio of rucaparib and methanesulfonic acid applied is
preferably in the range
of from about 1.0 (rucaparib): 0.8 to 1.2 (methanesulfonic acid), more
preferably from about
1.0 (rucaparib): 0.9 to 1.1 (methanesulfonic acid) and most preferably from
about 1.0
(rucaparib): 0.95 to 1.05 (methanesulfonic acid) e.g. the molar ratio is about
1.0 to 1Ø
The reaction is preferably carried out at a temperature in the range of from
about 0 to 60 C.
For example, as a first step the reaction mixture in step (i) above may be
heated to a temperature
in the range of from about 40 to 60 C in order to promote dissolution of
solid components
followed by cooling the mixture in step (ii) above to a temperature in the
range of from 0 to 25
C in order to initiate crystallization of rucaparib mesylate. The final
rucaparib mesylate
concentration of the mixture is preferably in the range of from about 20 to 80
g/L, more
preferably from about 40 to 60 g/L.
The mixture obtained in step (ii), may further be slurried, wherein slurrying
in the context of
the present invention relates to any motion of the mixture comprising
rucaparib mesylate, which
is caused by stirring, shaking and/or ultrasonic irradiation. Slurrying may be
performed for a
period in the range of from about 0.5 to 48 hours, preferably from about 1 to
24 hours, more
preferably from about 2 to 12 hours. The mixture may instead be allowed to
stand without
slurrying for a period in the range of from several hours to several days.
The obtained rucaparib mesylate crystals or at least a part thereof may
optionally be separated
from the mother liquor by any conventional method such as filtration or
centrifugation, most
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preferably by filtration. Optionally, the isolated crystals may be washed with
a solvent,
preferably with the same solvent or solvent mixture as used in step (i).
Finally, the rucaparib mesylate crystals may optionally be dried at a
temperature of about 60
C or less, preferably of about 50 C or less, more preferably of about 40 C
or less, for example
at about 40 C or at about room temperature. Drying may be performed for a
period in the range
of from about 1 to 72 hours, preferably from about 2 to 48 hours, more
preferably from about
4 to 24 hours and most preferably from about 6 to 18 hours. Drying may be
performed at
ambient pressure and/or under vacuum preferably at about 100 mbar or less,
more preferably at
about 50 mbar or less and most preferably at about 30 mbar or less, for
example at about 20
mbar or less.
Preferably, the rucaparib mesylate crystals are further equilibrated with an
atmosphere having
a relative humidity of about 75% and a temperature of about 40 C. This
treatment helps to
mature the crystalline material, yielding the highly crystalline rucaparib
mesylate form A of
example 1.
In another aspect, the invention relates to the use of the crystalline
rucaparib mesylate as defined
in any one of the embodiments described above for the preparation of a
pharmaceutical
composition.
In a further aspect the invention relates to a pharmaceutical composition
comprising the
crystalline rucaparib mesylate as defined in any one of the embodiments
described above or the
composition comprising the same as defined in anyone of the embodiments
described above,
preferably in an effective and/or predetermined amount and at least one
pharmaceutically
acceptable excipient.
In a preferred embodiment, the pharmaceutical composition of the present
invention is an oral
solid dosage form such as a tablet or a capsule. More preferably, the
pharmaceutical
composition of the present invention is a tablet, even more preferably a film-
coated tablet and
most preferably the pharmaceutical composition of the present invention is an
immediate-
release film-coated tablet.
The at least one pharmaceutically acceptable excipient is preferably selected
from the group
consisting of fillers, diluents, binders, disentegrants, lubricants and
glidants.
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More preferably, the at least one pharmaceutically acceptable excipient is
selected from the
group consisting of microcrystalline cellulose, sodium starch glycolate,
colloidal silicon
dioxide and magnesium stearate.
A preferred film-coated tablet of the present invention invention consists of
a tablet core
comprising the crystalline rucaparib mesylate as defined in any one of the
embodiments
described above or the composition comprising the same as defined in anyone of
the
embodiments described above, preferably in an effective and/or predetermined
amount,
microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide
and magnesium
stearate and a film-coating comprising a colorant, polyvinyl alcohol, titanium
dioxide,
polyethylene glycol/macrogol and talc.
Preferably, the present invention relates to a pharmaceutical composition as
defined in any one
of the embodiments described above, wherein the predetermined and/or effective
amount of the
crystalline rucaparib mesylate of the present invention is selected from the
group consisting of
200 mg, 250 mg and 300 mg, calculated as rucaparib free base.
More preferably, the pharmaceutical composition as defined in any one of the
embodiments
described above is administered twice daily such that a daily dose of 100 to
1200 mg, preferably
of 300 to 600 mg, for example of 300 mg, 400 mg, 500 mg or 600 mg, calculated
as rucaparib
free base is administered to a patient in need of such a treatment.
In another embodiment, the present invention relates to the pharmaceutical
composition as
defined in any one of the embodiments described above, wherein the
pharmaceutical
composition is stored at a temperature in the range of from 15 to 30 C,
preferably of from 20
to 25 C.
In another aspect, the present invention relates to the pharmaceutical
composition as defined
above for use as a medicament.
In still another aspect, the invention relates to the pharmaceutical
composition as defined above
for the treatment of cancer. Preferably, the cancer is selected from the group
consisting of
ovarian cancer, breast cancer, prostate cancer and pancreatic cancer. In a
further preferred
embodiment the invention relates to the pharmaceutical compostion as defined
above for the
treatment of solid tumours.
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The present invention is further illustrated by the following embodiments and
combinations of
embodiments resulting from the given dependencies and back-references:
1) Anhydrous crystalline 8-fluoro-2-(4-methylaminomethyl-pheny1)-1,3,4,5-
tetrahydro-
azepino[5,4,3-cd]indo1-6-one mesylate (rucaparib mesylate).
2) The crystalline rucaparib mesylate of item 1, characterized by the chemical
structure
according to formula (II)
0
F0 NH
HN /
41
/S----CH3
/
NH2+
formula (II).
3) The anhydrous crystalline rucaparib mesylate according to any one of items
1 or 2,
wherein the water content is at most 1.5 weight-%, the water content being
determined
according to Karl Fischer Coulometry.
4) The anhydrous crystalline rucaparib mesylate according to any one of items
1 or 2,
wherein the water content is at most 1.0 weight-%, the water content being
determined
according to Karl Fischer Coulometry.
5) The anhydrous crystalline rucaparib mesylate according to any one of items
1, 2, 3 or
4, wherein the anhydrous crystalline rucaparib mesylate takes up at most 2.0
weight %
water between 10% relative humidity and 90% relative humidity at 25 C.
6) The anhydrous crystalline rucaparib mesylate according to any one of items
1, 2, 3 or
4, wherein the anhydrous crystalline rucaparib mesylate takes up at most 1.5
weight %
water between 10% relative humidity and 90% relative humidity at 25 C.
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7) The anhydrous crystalline rucaparib mesylate according to any one of items
1, 2, 3 or
4, wherein the anhydrous crystalline rucaparib mesylate takes up at most 1.0
weight %
water between 10% relative humidity and 90% relative humidity at 25 C.
8) The anhydrous crystalline rucaparib mesylate according to any one of items
1 to 7,
5 characterized by having a powder X-ray diffractogram comprising
reflections at 2-Theta
angles of (9.9 0.2) , (12.2 0.2) and (22.5 0.2) , when measured at a
temperature
in the range of from 20 to 30 C with Cu-Kalpha radiation having a wavelength
of
0.15419 nm.
9) The anhydrous crystalline rucaparib mesylate according to item 8,
characterized by
10 having a powder X-ray diffractogram comprising further reflections at 2-
Theta angles
of (11.7 0.2) and/or (16.3 0.2) , when measured at a temperature in the
range of
from 20 to 30 C with Cu-Kalpha radiation having a wavelength of 0.15419 nm.
10) The anhydrous crystalline rucaparib mesylate according to any one of items
1 to 7,
characterized by having a powder X-ray diffractogram comprising reflections at
2-Theta
15 angles of (9.9 0.2) , (11.7 0.2) , (12.2 0.2) , (16.3 0.2) and
(22.5 0.2) , when
measured at a temperature in the range of from 20 to 30 C with Cu-Kalpha
radiation
having a wavelength of 0.15419 nm.
11) The anhydrous crystalline rucaparib mesylate according to any one of items
1 to 7,
characterized by having a powder X-ray diffractogram comprising reflections at
2-Theta
angles of (9.9 0.2) , (11.7 0.2) , (12.2 0.2) , (16.3 0.2) , (17.7
0.2) and (22.5
0.2) , when measured at a temperature in the range of from 20 to 30 C with Cu-
Kalpha radiation having a wavelength of 0.15419 nm.
12) The anhydrous crystalline rucaparib mesylate according to any one of items
1 to 7,
characterized by having a powder X-ray diffractogram comprising reflections at
2-Theta
angles of (9.9 0.2) , (11.7 0.2) , (12.2 0.2) , (16.3 0.2) , (17.7
0.2) , (20.7
0.2) and (22.5 0.2) , when measured at a temperature in the range of from
20 to 30
C with Cu-Kalpha radiation having a wavelength of 0.15419 nm.
13) The anhydrous crystalline rucaparib mesylate according to any one of items
1 to 7,
characterized by having a powder X-ray diffractogram comprising reflections at
2-Theta
angles of (9.9 0.2) , (11.7 0.2) , (12.2 0.2) , (15.0 0.2) , (16.3
0.2) , (17.7
0.2) , (20.7 0.2) and (22.5 0.2) , when measured at a temperature in the
range of
from 20 to 30 C with Cu-Kalpha radiation having a wavelength of 0.15419 nm.
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14) The anhydrous crystalline rucaparib mesylate according to any one of items
1 to 7,
characterized by having a powder X-ray diffractogram comprising reflections at
2-Theta
angles of (9.9 0.2) , (11.7 0.2) , (12.2 0.2) , (15.0 0.2) , (16.3
0.2) , (17.7
0.2) (19.8 0.2) , (20.7 0.2) and (22.5 0.2) , when measured at a
temperature in
the range of from 20 to 30 C with Cu-Kalpha radiation having a wavelength of
0.15419
nm.
15) The anhydrous crystalline rucaparib mesylate according to any one of items
1 to 7,
characterized by having a powder X-ray diffractogram comprising reflections at
2-Theta
angles of (9.9 0.2) , (11.7 0.2) , (12.2 0.2) , (13.9 0.2) , (15.0
0.2) , (16.3
0.2) , (17.7 0.2) (19.8 0.2) , (20.7 0.2) and (22.5 0.2) , when
measured at a
temperature in the range of from 20 to 30 C with Cu-Kalpha radiation having a
wavelength of 0.15419 nm.
16) The anhydrous crystalline rucaparib mesylate as defined in any one of
items 1 to 15,
characterized by having a powder X-ray diffractogram comprising no reflections
at 2-
Theta angles of (12.7 0.2) and/or (24.6 0.2) , when measured at a
temperature in
the range of from 20 to 30 C with Cu-Kalpha radiation having a wavelength of
0.15419
nm.
17) The anhydrous crystalline rucaparib mesylate as defined in any one of
items 1 to 16,
characterized by having a differential scanning calorimetric curve showing an
endothermic peak in the range of from 290 to 300 C, when measured at a
heating rate
of 10 K/min.
18) A composition comprising at least 90 weight-% of the anhydrous crystalline
rucaparib
mesylate as defined in anyone of items 1 to 17, based on the total weight of
the
composition.
19) The composition of item 18 characterized by a powder X-ray diffractogram
comprising
reflections at 2-Theta angles selected from the group consisting of (9.9
0.2) , (12.2
0.2) and/or (22.5 0.2) , when measured at a temperature in the range of
from 20 to
C with Cu-Kalpha radiation having a wavelength of 0.15419 nm.
20) Use of the anhydrous crystalline rucaparib mesylate as defined in any one
of items 1 to
30 17
or the composition as defined in item 18 or 19 for the preparation of a
pharmaceutical
composition.
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21) A pharmaceutical composition comprising the anhydrous crystalline
rucaparib mesylate
as defined in any one of items 1 to 17 or the composition as defined in items
18 or 19
and one or more pharmaceutically acceptable excipient(s).
22) The pharmaceutical composition as defined in item 21 for use as a
medicament.
23) The pharmaceutical composition as defined in item 22 for use in the
treatment of cancer.
24) The use according to item 23, wherein the cancer is selected from the
group consisting
of ovarian cancer, breast cancer, prostate cancer and pancreatic cancer.
EXAMPLES
The following non-limiting examples and analytical methods which have been
applied for the
generation of analytical data are illustrative for the disclosure and are not
to be construed as to
be in any way limiting for the scope of the invention.
Comparative example: production of rucaparib mesylate according to example A
of
W02004/087713A1
293 mg (0.91 mmol) of rucaparib base were suspended in 6 mL methanol. The
addition of
0.91mL methanesulfonic acid (1M, methanol, 0.91 mmol) resulted in a clear
yellow solution.
An additional amount of 11 mL methanol was added and the solution was then
concentrated
using a Rotavapor under reduced pressure. The appearance of a solid salt was
observed, but the
solid dissolved after the addition of 1.2 mL of water. The remaining methanol
was evaporated
(Rotavapor, reduced pressure) and the aqueous solution was frozen at -20 C.
The lyophilization
(0.12 mbar) of this sample resulted in a crystalline yellow solid (yield: 380
mg). TGA showed
a mass loss of 4.2% from room temperature to 175 C and Karl-Fischer titration
indicated a
water content of 4.9 +/- 0.3%. Thus, our reproduction of example A of
W02004/087713A1
produced a crystalline hydrate of rucaparib mesylate. Its powder X-ray
diffractogram was
clearly different from rucaparib mesylate form A of the present invention.
Example 1: composition comprising rucaparib mesylate form A
A vial was charged with rucaparib free base (60 mg, e.g. prepared according to
the procedure
disclosed in example IIII of WO 00/42040 Al), acetone (1.2 mL) and methane
sulfonic acid
(1.1 mol equivalents, 1M in THF). The reaction mixture was warmed to 50 C and
subsequently
cooled to 5 C at a cooling rate of -0.5 K/min. The reaction mixture was left
for 10 days at 5
C before the solid material was isolated and dried.
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Powder X-ray diffractometry
The powder X-ray diffractogram was collected using the same instrument and
settings as
described in example 2 below.
A powder X-ray diffractogram of the obtained composition comprising rucaparib
mesylate
form A of the present invention is displayed in figure 4 herein and the
corresponding reflection
list is provided in table 1 below. Additional reflections, which appear in the
composition
obtained from example 1 compared to the crystalline form of rucaparib mesylate
(form A) of
example 2 are highlighted in bold print.
Angle Angle Angle
[ 0.2 2-Theta] [ 0.2 2-Theta] [ 0.2 2-Theta]
7.8 17.7 24.6
9.9 18.4 25.2
11.7 18.7 25.3
12.2 19.1 25.6
12.7 19.3 26.4
13.7 19.9 26.9
13.9 20.8 27.2
14.3 21.4 28.1
15.1 22.3 28.9
16.3 22.6 30.0
16.9 23.0
17.4 23.5
Table 1: Reflection list of the composition obtained from example 1 between
2.0 and 32.0 2-Theta;
additional reflections, compared to the crystalline form of rucaparib mesylate
(form A) are highlighted
in bold print
Gravimetric moisture sorption
The gravimetric moisture sorption/desorption experiment was performed using
the same
instrument and settings as described in example 2. It was observed that some
peaks in the
powder x-ray diffractogram had changed upon exposure to moisture.
Example 2: crystalline rucaparib mesylate form A
The composition comprising crystalline rucaparib mesylate form A obtained from
example 1
above was stored open in a climate chamber at a temperature of 40 C and a
relative humidity
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of 75% for 7 days. Phase pure crystalline rucaparib mesylate form A was
obtained
quantitatively.
Powder X-ray diffractometry
The powder X-ray diffractogram was collected on a Panalytical Empyrean
diffractometer, using
Cu Kalpha radiation (45 kV, 40 mA) having a wavelength of 0.15419 nm, in
transmission
geometry. A 0.5 slit, 4 mm mask and 0.04 rad Soller slits with a focusing
mirror were used on
the incident beam side. A Pixcel31 detector, placed on the diffracted beam
side, was fitted with
a receiving slit and 0.04 rad Soller slit. The software used for data
collection was X'Pert Data
Collector using X'Pert Operator Interface. The sample was prepared and
analysed in a metal
well-plate in transmission mode. X-ray transparent film was used between the
metal sheets on
the metal well-plate, and the powder (approximately 1 ¨ 2 mg) was used as
received. The scan
mode for the metal plate used the gonio scan axis. The details for the
standard screening data
collection method are:
= angular range: 2.5 to 32.0 2-Theta
= step size: 0.0130 2-Theta
= collection time: 12.75 s/step (total collection time 2.07 min)
A typical precision of the 2-Theta values is in the range of 0.2 2-Theta.
Thus, the reflection
of the rucaparib mesylate form A of the present invention that appears for
example at 22.6 2-
Theta can appear between 22.4 and 22.8 2-Theta on most X-ray diffractometers
under
.. standard conditions.
A representative powder X-ray diffractogram of the rucaparib mesylate form A
of the present
invention is displayed in figure 1 herein and the corresponding reflection
list is provided in
table 2 below.
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Angle Angle Angle
[ 0.2 2-Theta] [ 0.2 2-Theta] [ 0.2 2-Theta]
9.9 18.6 25.1
11.7 19.0 25.3
12.2 19.2 25.5
13.9 19.8 26.3
14.3 20.7 26.9
15.0 21.4 27.1
16.3 22.2 28.0
17.3 22.5 28.8
17.7 23.0 29.9
18.3 23.4
Table 2: Reflection list of rucaparib mesylate form A of the present invention
obtained from example
2 between 2.0 and 32.0 2-Theta
Differential scanning calorimetry
5 Differential scanning calorimetry was performed with a TA Instruments
Discovery DSC
equipped with a 50 position auto-sampler. A defined amount of sample (in the
range of form
0.5-3.0 mg) was weighed into a pin-holed aluminium pan, and heated at 10
K/min from 25 to
350 C. A purge of dry nitrogen at 50 mL/min was maintained over the sample.
The instrument
control software was TRIOS and the data were analysed using TRIOS or Universal
Analysis.
10 The differential scanning calorimetric curve shows no thermal event
until an endothermic peak
having an onset temperature of about 294 C and a peak temperature of about
297 C occurs,
which is due to the melting of the sample. A representative differential
scanning calorimetric
curve of rucaparib mesylate form A of the present invention is displayed in
figure 2 herein.
Thermogravimetric analysis
15 Data were collected on a TA Instruments Discovery TGA, equipped with a
25 position auto-
sampler. An accurately weighed amount of sample (5-10 mg) was loaded onto a
pre-tared
aluminium pan and heated at 10 K/min from 25 to 350 C. A nitrogen purge (25
mL/min) was
maintained over the sample.
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The crystalline form of rucaparib mesylate (form A) of the present invention
showed a mass
loss of only about 0.8 weight%, based on the initial weight of the sample up
to a temperature
of 250 C indicating the presence of an anhydrous and solvent free form.
Gravimetric moisture sorption
The gravimetric moisture sorption/desorption experiment was performed on a SMS
DVS
Intrinsic moisture sorption analyser, controlled by DVS Intrinsic Control
software. The sample
temperature was maintained at 25 C by the instrument controls. The humidity
was controlled
by mixing streams of dry and wet nitrogen, with a total flow rate of 200
mL/min. The relative
humidity was measured by a calibrated Rotronic probe (dynamic range of 1.0 -
100% relative
humidity), located near the sample. The weight change, (mass relaxation) of
the sample as a
function of % relative humidity was constantly monitored by a microbalance
(accuracy 0.005
mg). 5-30 mg sample was placed in a tared mesh stainless steel basket under
ambient
conditions. The sample was loaded and unloaded at 40% relative humidity and 25
C. A
moisture sorption isotherm was performed as outlined below (2 scans per
complete cycle). The
standard isotherm was performed at 25 C at 10% relative humidity intervals
over a 0-90%
relative humidity range. A double cycle (4 scans) was carried out with the
parameters listed
below. Data analysis was carried out within Microsoft Excel using the DVS
Analysis Suite.
adsorption ¨ scan 1: 40 ¨ 90
desorption, adsorption ¨ scan 2: 90 ¨ 0, 0 ¨ 40
intervals (% relative humidity): 10
number of scans: 4
flow rate (mL/min): 200
temperature ( C): 25
stability ( C/min): 0.2
sorption time (hours): 6-hour time out
The corresponding gravimetric moisture sorption/desorption curves are
presented in figure 3
herein. The powder X-ray diffractograms of the sample before and after the
measurement
showed good consistency. The absence of a significant hysteresis between the
sorption and
desorption curves also indicates that no significant structural changes
occurred during the
experiment. The reversible water uptake in the range of from 0 to 90% relative
humidity was
below 0.9 weight-%, indicating that almost no interaction with water vapor
took place.
Crystalline rucaparib mesylate form A of the present invention can therefore
be classified as
non-hygroscopic.
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Aqueous solubility
The aqueous solubility was determined by suspending sufficient amount of
rucaparib mesylate
form A in water to give a maximum final concentration of? 18 mg/mL based on
the amount of
dissolved rucaparib free form. The suspension was equilibrated at 25 C on a
Heidolph plate
shaker set to 750 rpm for 24 hours. The pH of the saturated solution was then
measured and the
suspension filtered through a glass fibre C filter (particle retention 1.2
micrometer) and diluted
appropriately. Quantitation was done by HPLC with reference to a standard
solution of
approximately 0.15 mg/mL in DMSO. Different volumes of the standard, diluted
and undiluted
sample solutions were injected. The solubility was calculated using the peak
areas determined
by integration of the peak found at the same retention time as the principal
peak in the standard
injection. The following HPLC method was used:
Type of method reverse phase with gradient elution
Phenomenex Luna, C18 (2) 5 micrometer 50
column
x mm
column temperature ( C) 25
standard injections (microliter) 1, 2, 3, 4, 5, 7
test injections (microliter) 1, 2, 3, 10 ,15 , 20
detection: wavelength, bandwidth (nm) 260, 90
flow rate (mL/min 2
phase A 0.1% trifluoroacetic acid in water
phase B 0.085% trifluoroacetic acid in
acetonitrile
timetable time (min) % phase A % phase B
0.0 95 5
1.0 80 20
2.3 5 95
3.3 5 95
3.5 95 5
4.4 95 5
The aqueous solubility of the crystalline rucaparib mesylate form A of the
present invention
was determined to be > 18 mg/mL (pH 3.6).
