Note: Descriptions are shown in the official language in which they were submitted.
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WO 2012/062916
PCT/EP2011/069969
Crystalline solifenacin succinate
The present invention relates to crystalline solifenacin succinate, its use, a
method
for manufacturing solifenacin succinate, a solifenacin succinate that can be
manufac-
tured by that method, and its use.
Background of the invention
Solifenacin is a medicinal agent from the pharmacotherapeutic group of
urological
spasmolytic agents for the treatment of symptoms of a hyperactive bladder and
is
described in the international patent application WO 96/020194. Solifenacin is
used
pharmaceutically as solifenacin succinate, which is also known as butane dioic
acid:
(I S)-
(3R)-1-azabicyclo [2.2.2] oct-3-y1 3 ,4-dihydro-1-pheny1-2(1H) - isoquinoline
carboxylate (1 : 1). Solifenacin is licensed for the symptomatic treatment of
urge
incontinence or pollakiuria and imperative urge micturition, which can occur
in
patients with hyperactive bladder syndrome. Solifenacin is a competitive,
specific,
cholinergic receptor antagonist.
The mechanism of action of solifenacin is based on the fact that the bladder
is inner-
vated by parasympathetic, cholinergic nerves. Acetyl choline acts via
muscarine re-
ceptors, mainly via subtype M3, causing a contraction of the smooth muscle of
the
Musculus detrusor. Solifenacin inhibits the subtype M3 muscarine receptor
competi-
tively and specifically, since it only exhibits low or no affinity for various
other
receptors and ion channels.
Solifenacin succinate is slightly soluble in water and moderately soluble in
organic
solvents. A crystalline modification of solifenacin succinate and amorphous
solifen-
acin succinate are known in the state of the art. The amorphous substance is
chemi-
cally unstable and easily forms decomposition products.
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The crystalline modification of solifenacin succinate was first described in
the Euro-
pean patent application EP 1 832 288 Al. Solifenacin succinate is known to
crystal-
lise from organic solvents and mixtures of solvents. In EP 1 832 288 Al, for
exam-
ple, mixtures of solvents such as ethyl acetate/Et0H were used. In all the
published
solvents and mixtures of solvents such as ethyl acetate/ethanol or ethyl
acetate/ace-
tone solifenacin succinate crystallises in the form of long needles. This
acicular soli-
fenacin succinate tends to agglutinate, which gives rise to a number of
technological
problems in the production of pharmaceutical compositions and formulations.
These
technological problems are ultimately also due to the poor flow properties of
the
acicular crystallised solifenacin succinate resulting from the agglutination.
Specific-
ally, this leads, for example, to an uneven content of solifenacin succinate
in a phar-
maceutical composition or formulation or to the delamination and spatting of
tablets
containing acicular solifenacin succinate of this kind, i.e. tablets of this
kind tend to
separate into layers.
WO 2009/139002 A2 describes methods for preparing solifenacin succinate. The
solifenacin succinate obtained is crystallised from ethyl acetate and/or
acetone. In
the process, however, the product is obtained in the form of long needles, but
these
are disadvantageous because of their poor flow and processing properties.
US 2008/0242697 Al describes methods for synthesising solifenacin succinate.
The
solifenacin succinate obtained is crystallised from acetone, methanol or a
mixture of
methanol and acetone. In the process, however, the product is obtained in the
form
of long needles, but these are disadvantageous because of their poor flow and
pro-
cessing properties.
EP 2 088 148 A2 describes methods for preparing solifenacin and its salts,
such as
solifenacin succinate. The solifenacin succinate obtained is crystallised from
a mix-
ture of ethanol and ethyl acetate. In the process, however, the product is
obtained in
the form of long needles, but these are disadvantageous because of their poor
flow
and processing properties.
US 2008/0114028 Al describes methods for preparing polymorphous forms of soli-
fenacin succinate, the solifenacin succinate being crystallised from solvents
and
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mixtures of solvents, such as mixtures of methanol and acetone. In the
process, how-
ever, the product is obtained in the form of long needles, but these are
disadvantage-
ous because of their poor flow and processing properties. Action is taken
against this
problem in US 2008/0114028 Al by adding glidants, such as silicate, talcum,
starch
or calcium phosphate, though this is disadvantageous for economic reasons,
inter
alia, which limits the possible uses of the product.
US 2009/0099365 Al describes methods for preparing solifenacin succinate,
which
is crystallised from solvents and mixtures of solvents, such as ethyl acetate
or ace-
tone. In the process, however, the product is obtained in the form of long
needles,
but these are disadvantageous because of their poor flow and processing
properties.
The solifenacin succinate crystals prepared using the methods described above
which are known from the state of the art are thus obtained in the form of
long
needles, which correspond to the crystals shown in Figures 10 and 11 and have
an
average axial ratio of > 10 : 1. The methods known from the state of the art
for pre-
paring solifenacin succinate thus lead to products which possess the
disadvantageous
product and processing properties described above.
It is recognised by the experts working in the field that these technological
problems
either make further technical measures necessary, such as adding
microcrystalline
cellulose in order to avoid the spalling or delamination of such tablets, or
entail a
limitation of the pharmaceutical compositions containing this form of
solifenacin
succinate. One example of a limitation is that no pharmaceutical formulations
con-
taining solifenacin succinate of this kind are manufactured in which it is
necessary to
maintain a uniform content of solifenacin succinate within narrow tolerances.
Problem of the invention
The present invention is therefore based on the problem of providing a form of
soli-
fenacin succinate which possesses better flow properties than the acicular
crystalline
solifenacin succinate known in the state of the art.
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,
Description of the invention
This and other problems are solved by the subject matter of the attached
independent
claims. Preferred embodiments can be gathered from the dependent claims which
are likewise attached.
In particular, these and further problems are solved by the aspects and
embodiments
of the present invention described below.
In a first aspect, the problems are solved in accordance with the invention by
a crys-
talline solifenacin succinate wherein the solifenacin succinate has an average
axial
ratio of 5 : 1 or less, preferably an average axial ratio of 5 : 1 to 1 : 1,
particularly
preferably an average axial ratio of 1 : 1 and at least one of the following
properties:
a) a particle size d 0.9 < 200 [tm;
b) an average particle size of about 2 to 40 tun; and
c) peaks in the X-ray powder diffractogram at 3.7; 11.1; 18.6; 21.8 2 0
0.2 20.
This is also a first embodiment of the first aspect.
In a second embodiment of the first aspect, which is also an embodiment of the
first
embodiment of the first aspect, it is contemplated that the solifenacin
succinate has
a) an average axial ratio of 5: 1 or less, preferably an average axial
ratio
of 5 : 1 to 1 : 1, particularly preferably an average axial ratio of 1 : 1;
b) a particle size d 0.9 < 200 p.m; and
c) an average particle size of about 2 to 40 vim.
In a third embodiment of the first aspect, which is also an embodiment of the
first
embodiment of the first aspect, it is contemplated that the solifenacin
succinate has
a) an average axial ratio of 5 : 1 or less, preferably an average axial
ratio
of 5 : 1 to 1 : 1, particularly preferably an average axial ratio of 1 : 1;
b) a particle size d 0.9 < 200 p.m; and
c) peaks in the X-ray powder diffractogram at 3.7; 11.1; 18.6; 21.8 2 0
0.2 20.
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In a fourth embodiment of the first aspect, which is also an embodiment of the
first
embodiment of the first aspect, it is contemplated that the solifenacin
succinate has
a) an average axial ratio of 5 : 1 or less, preferably an average axial
ratio
of 5 : 1 to 1 : 1, particularly preferably an average axial ratio of 1 : 1;
b) an average particle size of about 2 to 40 p.m; and
c) peaks in the X-ray powder diffractogram at 3.7; 11.1; 18.6; 21.8 2
0.2 20.
In a fifth embodiment of the first aspect, which is also an embodiment of the
first
embodiment of the first aspect, it is contemplated that the solifenacin
succinate has
the following properties:
a) an average axial ratio of 5 : 1 or less, preferably an average axial
ratio
of 5 : 1 to 1 : 1, particularly preferably an average axial ratio of 1 : 1;
b) a particle size d 0.9 < 200 j_tm;
c) an average particle size of about 2 to 40 ilm; and
d) peaks in the X-ray powder diffracto gram at 3.7; 11.1; 18.6; 21.8 2
0.2 20.
In a further preferred embodiment of the first aspect, which is also an
embodiment
of the first embodiment of the first aspect, it is contemplated that the
solifenacin
succinate has the following properties:
(a) an average axial ratio of 5 : 1 or less, preferably an average axial
ratio
of 5 : 1 to 1 : 1, particularly preferably an average axial ratio of 1 : 1
and
(b) an average particle size of about 2 to 40 lam, preferably 5 to 30 p.m.
In a second aspect, the problems are solved in accordance with the invention
by a
crystalline solifenacin succinate wherein the solifenacin succinate has an
average
axial ratio of 5 : 1 or less, preferably an average axial ratio of 5 : 1 to 1
: 1, particu-
larly preferably an average axial ratio of 1 : 1. This is also a first
embodiment of the
second aspect.
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In a third aspect, the problems are solved in accordance with the invention by
a crys-
talline solifenacin succinate wherein the solifenacin succinate has a particle
size d
0.9 < 200 pm, preferably d 0.9 5_ 150 p.m and particularly preferably d 0.9 5_
100 m.
This is also a first embodiment of the third aspect.
In a fourth aspect, the problems are solved in accordance with the invention
by a
crystalline solifenacin succinate wherein the solifenacin succinate has an
average
particle size of about 2 to 40 m, preferably 5 to 30 p.m. This is also a
first embodi-
ment of the fourth aspect.
In a fifth aspect, the problems are solved in accordance with the invention by
a crys-
talline solifenacin succinate wherein the solifenacin succinate has peaks in
the X-ray
powder diffractogram at 3.7; 11.1; 18.6; 21.8 02 0 0.2 20. This is also a
first em-
bodiment of the fifth aspect.
In an embodiment of the first, second, third, fourth and fifth aspects, which
is also an
embodiment of any embodiment of the first, second, third, fourth and fifth
aspects, it
is contemplated that the particle size is determined by means of laser
diffraction.
In an embodiment of the first, second, third, fourth and fifth aspects, which
is also an
embodiment of any embodiment of the first, second, third, fourth and fifth
aspects, it
is contemplated that d 0.9 is < 150 IM1 and preferably d 0.9 is < 1001AM.
In an embodiment of the first, second, third, fourth and fifth aspects, which
is also an
embodiment of any embodiment of the first, second, third, fourth and fifth
aspects, it
is contemplated that the average particle size is about 5 to 30 m.
In an embodiment of the first, second, third, fourth and fifth aspects, which
is also an
embodiment of any embodiment of the first, second, third, fourth and fifth
aspects, it
is contemplated that the average particle size is determined by means of laser
dif-
fraction.
In an embodiment of the first, second, third, fourth and fifth aspects, which
is also an
embodiment of any embodiment of the first, second, third, fourth and fifth
aspects, it
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is contemplated that the the X-ray powder diffractogram is produced in Bragg-
Bren-
tano geometry over a range of angles of 3 - 45 and a copper cathode.
In an embodiment of the first, second, third, fourth and fifth aspects, which
is also an
embodiment of any embodiment of the first, second, third, fourth and fifth
aspects, it
is contemplated that the X-ray powder diffractogram is substantially the X-ray
pow-
der diffractogram shown in Fig. 1.
In an embodiment of the first, second, third, fourth and fifth aspects, which
is also an
embodiment of any embodiment of the first, second, third, fourth and fifth
aspects, it
is contemplated that the crystalline solifenacin succinate includes more than
10 % by
weight of solifenacin succinate with an X-ray powder diffractogram wherein the
X-
ray powder diffractogram has peaks at 3.7; 11.1; 18.6; 21.8 2 0 + 0.2 20.
In an embodiment of the first, second, third, fourth and fifth aspects, which
is also an
embodiment of any embodiment of the first, second, third, fourth and fifth
aspects, it
is contemplated that the crystalline solifenacin succinate is a micronised
solifenacin
succinate.
In an embodiment of the first, second, third, fourth and fifth aspects, which
is also an
embodiment of any embodiment of the first, second, third, fourth and fifth
aspects, it
is contemplated that the crystalline solifenacin succinate of the invention is
intended
and/or is suitable for the production of a medicament, wherein it is
contemplated in a
further embodiment that the medicament is a solid dosage form. In an even more
preferred embodiment, it is contemplated that the solid dosage form is a
tablet, pref-
erably a divisible tablet. The medicament can be used in its various
embodiments or
is suitable for use in the treatment and/or prevention of a disease or
condition,
wherein the disease and/or the condition is selected from the group comprising
symptoms of a hyperactive bladder, urge incontinence, pollakiuria and
imperative
urge micturition.
In an embodiment of the first, second, third, fourth and fifth aspects, which
is also an
embodiment of any embodiment of the first, second, third, fourth and fifth
aspects, it
is contemplated that the solifenacin succinate of the invention is suitable
for or is
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used for the production of a medicament, wherein the medicament is or can be a
solid dosage form in its various forms described herein or known to experts in
the
field. In these embodiments for their part, it is contemplated that the dosage
form
has a content of < 5 mg solifenacin succinate, preferably < 2.5 mg solifenacin
suc-
cinate and particularly preferably < 1 mg solifenacin succinate.
In an embodiment of the first, second, third, fourth and fifth aspects, which
is also an
embodiment of any embodiment of the first, second, third, fourth and fifth
aspects, it
is contemplated that the crystalline solifenacin succinate is used or is
suitable for use
in a method for the treatment of a living creature, preferably a human being,
wherein
the method comprises administering a pharmaceutically effective amount of the
crystalline solifenacin succinate to the living creature.
In a sixth aspect, the problems are solved in accordance with the invention by
the
use of the crystalline solifenacin succinate of the present invention and
especially in
accordance with any embodiment of the first, second, third, fourth and fifth
aspects
for the production of a medicament. This is also a first embodiment of the
first as-
pect.
In a second embodiment of the sixth aspect, it is contemplated that the
medicament
is suitable for use or is used in the treatment and/or prevention of a disease
or condi-
tion, wherein the disease and/or the condition is selected from the group
comprising
symptoms of a hyperactive bladder, urge incontinence, pollakiuria and
imperative
urge micturition.
In a seventh aspect, the problems are solved in accordance with the invention
by a
method for the production of crystalline solifenacin succinate, wherein it is
contem-
plated that crystalline solifenacin succinate is used as the starting
material, wherein
the solifenacin succinate used as the starting material is a crystalline
solifenacin suc-
cinate which is different from the crystalline solifenacin succinate according
to any
embodiment of the first, second, third, fourth and fifth aspects of the
present inven-
tion, and that the starting material is subjected to a comminution step,
wherein the
particle size and/or the average particle size and/or the axial ratio of the
starting
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material is reduced in the comminution step. This is also a first embodiment
of the
seventh aspect.
In a second embodiment of the seventh aspect, which is also an embodiment of
the
first embodiment of the seventh aspect, it is contemplated that the
comminution step
comprises a measure selected from the group comprising sublimation, grinding,
mic-
ronising and wet micronising.
In a third embodiment of the seventh aspect, which is also an embodiment of
the
first and second embodiments of the seventh aspect, it is contemplated that
the soli-
fenacin succinate to be produced is a crystalline solifenacin succinate
according to
any embodiment of the first, second, third, fourth, fifth and sixth aspects of
the pres-
ent invention.
In a fourth embodiment of the seventh aspect, which is also an embodiment of
the
first, second and third embodiments of the seventh aspect, it is contemplated
that the
crystalline solifenacin succinate used as the starting material has peaks in
the X-ray
powder diffractogram at 3.7; 11.1; 18.6; 21.8 2 0 0.2 28.
In a fifth embodiment of the seventh aspect, which is also an embodiment of
the
first, second, third and fourth embodiments of the seventh aspect, it is
contemplated
that the comminution step is performed to the extent that or until the average
axial
ratio of the solifenacin succinate is 5 : 1 or less, preferably the average
axial ratio of
the solifenacin succinate is from 5: 1 to 1 : 1 and particularly preferably
the average
axial ratio is 1 : 1.
In an eighth aspect, the problems are solved in accordance with the invention
by a
crystalline solifenacin succinate which is obtainable by a method according to
the
seventh aspect of the present invention and its various embodiments. This is
also a
first embodiment of the eighth aspect.
In a second embodiment of the eighth aspect, which is also an embodiment of
the
first embodiment of the eighth aspect, it is contemplated that the crystalline
solifena-
cin succinate is intended or suitable for use as described herein in
connection with
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the first, second, third, fourth, fifth and sixth aspects of the present
invention and its
various embodiments.
The form of solifenacin succinate and especially crystalline solifenacin
succinate de-
scribed in the context of the present invention is also referred to herein as
solifenacin
succinate in accordance with the invention or the solifenacin succinate of the
inven-
tion.
The present inventor has surprisingly found a new form of solifenacin
succinate,
which possesses at least one of the following four properties:
a) an average axial ratio of 5 : 1 or less, preferably an average axial
ratio
of 5 : 1 to 1 : 1, particularly preferably an average axial ratio of 1 : 1;
b) a particle sized 0.9 < 100 pm;
c) an average particle size of about 2 to 40 pm; and
d) peaks in the X-ray powder diffractogram at 3.7; 11.1; 18.6; 21;8 2 ID
8 0;2 20.
This new form of solifenacin succinate is also referred to herein as
solifenacin suc-
cinate in accordance with the invention or the solifenacin succinate of the
invention.
In addition, the present inventor has surprisingly found that this new form of
solifen-
acin succinate exhibits very good flow properties with the axial ratio and/or
small
particle size specified. Without wishing to be committed to this in the
following, the
reason for this property of the solifenacin of the invention appears to be
that the
acicular shape of the solifenacin is less pronounced than in the prior-art
solifenacin.
This property preferably finds expression in a comparatively low axial ratio,
or an
axial ratio which is lower than that of the prior-art solifenacin. The
technical teach-
ing provided in the context of the present invention is therefore
diametrically diffe-
rent from the technical teaching of the state of the art in this respect, and
the techni-
cal effect achieved with the technical teaching of the present invention is
surprising
in that the opposite route was proposed and adopted in the state of the art in
order to
increase the flowability of solifenacin succinate. According to Nagakawa S. et
al.
("The abstract of Lectures at the Memorial Symposium for the Foundation of the
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Japan Process Chemistry Association (held on July 4 to July 5, 2002), pp. 85-
86", as
cited in EP 1 726 304 Al), the fluidity of solifenacin succinate can be
improved by
increasing the particle size and especially also by means of a comparatively
large
axial ratio. According to Nagakawa et al., crystals with a size of 50 - 100 um
exhibit
poor fluidity; crystals with a size of several hundred um, however, exhibit
consider-
ably improved fluidity.
Without wishing to be committed to this in the following, the inventors
presume that
the advantageous properties of the crystalline solifenacin in accordance with
the
present invention and especially of the crystalline solifenacin succinate in
accor-
dance with the present invention are due to the fact that the axial ratio of
the crystal-
line solifenacin in accordance with the present invention is reduced compared
to the
axial ratio of solifenacin succinate according to the state of the art. Such a
reduction
in the axial ratio of crystalline solifenacin succinate can be achieved by,
for exam-
ple, subliming, grinding, micronising and wet micronising a suitable starting
materi-
al. It is preferable to use as the starting material a crystalline solifenacin
succinate
whose peaks in the X-ray powder diffractogram correspond to those of the
crystal-
line solifenacin succinate in accordance with the present invention. In a
preferred
embodiment, the peaks in the X-ray powder diffractogram are at 3.7; 11.1;
18.6;
21.8 02 8 0.2 20.
In addition, it has also been surprisingly found in the present context that
the combi-
nation of the axial ratio of the invention with the particle size in
accordance with the
invention leads to a particularly advantageous flow behaviour and to
particularly
good processing properties of the solifenacin succinate. A further reduction
of the
particle size of the solifenacin succinate to d 0.9 < 10 um and/or of the
average par-
ticle size to < 5 urn, especially <2 urn, led once again to a deterioration of
the flow
behaviour despite the average axial ratio in accordance with the invention. It
is
therefore preferable that the solifenacin succinate of the invention should
have an
axial ratio as described herein, and also a particle size distribution of d
0.1 > 5 urn, d
0.5 of < 150 um and d 0.9 <200 urn and/or an average particle size of >2 um,
prefe-
rably >5 urn.
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This form of crystalline solifenacin succinate overcomes the disadvantages of
acicu-
lar crystalline solifenacin succinate described in the state of the art. The
solifenacin
succinate according to the present invention is characterised, especially with
regard
to its handling properties, by the fact that, compared to the acicular
crystalline form
of solifenacin succinate, it has better flow properties. Better flow
properties of this
kind find expression in, among other things, improved aggregative properties
and a
reduced tendency to agglomerate, and also greater fluidity. In addition, the
solifena-
cin succinate of the invention exhibits greater bulk density.
The axial ratio, referred to herein as the average axial ratio, is determined
by meas-
uring the solifenacin succinate crystals in their axial and longitudinal
directions
using light-optical microscope images. For this purpose, a large number of
solifena-
cin succinate crystals, which are selected at random from a sample, are
measured
using light-optical microscope images, and their extension in the axial and
longitudi-
nal directions is determined. The extension in the longitudinal direction in
this con-
text corresponds to the maximum distance between two opposing points of a
solifen-
acin succinate crystal, while the extension in the axial direction corresponds
to the
minimum distance between two opposing points transversely to the longitudinal
direction, measured at the centre point of the longitudinal axis. In order to
arrive at a
meaningful statement, the average axial ratio is determined by means of the
average
of the results obtained from at least 10 crystals selected at random.
The properties of the solifenacin succinate of the invention mean that it can
advan-
tageously be used especially in the production of tablets and specifically in
the pro-
duction of tablets by means of direct compression, which is one of the most
impor-
tant, economical and elegant methods for producing tablets. The flowability of
the
powder mixtures is a precondition for direct compression, which is also known
as
direct tabletting, because it is essential for the powder to flow evenly and
in a con-
trolled manner into the tabletting machines for controlled processing of the
tablets in
the tablet presses. If, as when solifenacin succinate particles according to
the state of
the art are used, the mixture to be compressed into tablets does not flow
smoothly,
tablets which are too light may be formed. In addition, the components can
separate.
Non-uniform mixtures lead to fluctuations in the content of active agent. This
means
that with the solifenacin succinate according to the invention, a form of
solifenacin
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succinate is provided which is suitable for the production of pharmaceutical
compo-
sitions and can be used for that purpose, the pharmaceutical compositions
being in
particular ones which have a small content of solifenacin succinate, which
contain
an amount of solifenacin succinate where the amount may only fluctuate within
nar-
row tolerances between the individual compositions and especially between the
indi-
vidual tablets, or which must exhibit a uniform distribution of the active
agent, i.e.
the solifenacin succinate, within the individual composition and especially
within a
single tablet.
Pharmaceutical dosage forms in which the solifenacin succinate of the
invention can
be used in a particularly advantageous manner are divisible tablets and scored
tab-
lets, which are known to those skilled in the art and which can be produced by
the
latter in the light of the technical teaching provided herein, using the
solifenacin
succinate of the present invention. Dosage forms of this kind are described
inter alia
in Bauer / Fromming / Fiihrer "Lehrbuch der pharmazeutischen Technologie"
(Text-
book of pharmaceutical technology), chapter on "Tablets", or the European
Pharma-
copoeia 6.1 in the chapter "Tablets".
How the particle size is determined is known to those skilled in the art and
is de-
scribed by way of example in the example section herein and in the European
Phar-
macopoeia 6.1, Chap. 2.9.31 "Particle size analysis by laser light
diffraction". Typ-
ically, the particle size is determined by means of laser diffraction in
silicone oil. It
is typical in this context to use a Malvern Mastersizer 2000 to determine the
particle
size. In order to analyse the individual particles and not the agglomerates,
the sus-
pension of solifenacin succinate and silicone oil is treated for one minute in
an ultra-
sonic bath.
As those skilled in the art will know, the d(0.5) or d 0.5 value is the value
at which
50 % of the particles are below a size stated after it. The d(0.9) or d 0.9
value is the
value at which the 90 % of the particles are below a size stated after it.
How the average particle size is determined is known to those skilled in the
art and
is described by way of example in the example section herein.
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How an X-ray powder diffractogram is produced is known to those skilled in the
art
and is described by way of example in the European Pharmacopoeia 6.1, Chap.
2.9.33 "Characterisation of crystalline and partially crystalline solids by X-
ray pow-
der diffraction" and briefly in the example section herein.
It will be appreciated by those skilled in the art that the parameters which
character-
ise the solifenacin succinate of the invention are determined or can be
determined,
where not otherwise specified, using the various corresponding methods
described
or disclosed herein.
Description of the Figures and Examples
The present invention will now be illustrated in more detail with reference to
the fol-
lowing Figures and Examples, from which further features, embodiments and
advan-
tages of the invention can be seen, though without limiting the subject matter
of the
present invention. There,
Fig. 1 shows the X-ray powder diffractogram of the solifenacin succinate of
the invention;
Fig. 2 shows a light-optical microscope image of solifenacin succinate crys-
tals as obtained in accordance with Example 1 (10-fold magnification
in paraffin oil);
Fig. 3 shows a light-optical microscope image of solifenacin succinate crys-
tals as obtained in accordance with Example 2 (40-fold magnification
in paraffin oil);
Fig. 4 shows a diagram representing the particle size distribution of solifen-
acin succinate in accordance with Example 2, as measured by laser
diffraction;
Fig. 5 shows a light-optical microscope image of solifenacin succinate crys-
tals as obtained in accordance with Example 3;
Fig. 6 shows a diagram representing the particle size distribution of solifen-
acin succinate in accordance with Example 3, as measured by laser
diffraction;
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Fig. 7 shows a light-optical microscope image of solifenacin succinate crys-
tals as obtained in accordance with Example 4;
Fig. 8 shows a diagram representing the particle size distribution of solifen-
acin succinate in accordance with Example 4, as measured by means
of laser diffraction;
Fig. 9 shows a light-optical microscope image of solifenacin succinate crys-
tals as obtained in accordance with the technical teaching of EP 1 714
956 Al;
Fig. 10 shows a light-optical microscope image of solifenacin succinate crys-
tals as obtained in accordance with Comparative Example 2 after re-
crystallisation in ethyl acetate (10-fold magnification); and
Fig. 11 shows a light-optical microscope image of solifenacin succinate crys-
tals as obtained in accordance with Comparative Example 3 after re-
crystallisation in a mixture of ethyl acetate and acetone.
The axial ratio of the solifenacin succinate crystals was determined by
measuring 10
crystals selected at random, using the microscope images shown in the Figures.
Example 1: Production of solifenacin succinate in accordance with the inven-
tion
0.56 g crystalline solifenacin succinate with Bragg peaks at 3.7; 11.1; 18.6;
21.8 2
0 0.2 20 were dissolved in 2.3 ml ethyl acetate and 0.8 ml ethanol in a
round-
bottomed flask. After that, the round-bottomed flask containing the solution
was
shock-chilled to 0 C in an ice water bath in a freezer. A solid cake formed
in the
round-bottomed flask. The cake was evacuated in the flask at 90 C and 20 mbar
in
a vacuum drying cabinet. The cake was still solid and was easy to scrape out
of the
flask. The crystals had good flow properties.
The crystalline solifenacin succinate obtained in this way was examined under
a
light-optical microscope; the light-optical microscopic image is shown as Fig.
2. The
axial ratio found was approx. 2.5 : 1.
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An X-ray powder diffractogram of the crystalline solifenacin succinate
obtained in
this way was produced, which is shown as Fig. 1.
Example 2: Production of solifenacin succinate in accordance with the inven-
tion
Acicular crystalline solifenacin succinate with Bragg peaks at 3.7; 11.1;
18.6; 21.8
2 0 0.2 20 was placed in a hand-held mortar and ground with a pestle for
approx.
1 minute. The ground substance had good flow properties and did not form
lumps.
The crystalline solifenacin succinate obtained in this way was examined under
a
light-optical microscope; the light-optical microscopic image is shown as Fig.
3. The
axial ratio found was approx. 1 : 1.
The particle size distribution of the crystalline solifenacin succinate
obtained in this
way was determined by laser diffraction. The result is shown in Fig. 4.
Example 3: Production of solifenacin succinate in accordance with the inven-
tion
Crystalline solifenacin succinate with Bragg peaks at 3.7; 11.1; 18.6; 21.8
2 0
0.2 20 was placed in a type MM 301 Retsch vibration grinding mill and ground
with a ball for approx. 2 minutes at 10 Hz in a metal container intended for
that
apparatus.
The crystalline solifenacin succinate obtained in this way was examined under
a
light-optical microscope; the light-optical microscopic image is shown as Fig.
5. The
axial ratio found was approx. 1.5 : 1.
The particle size distribution of the crystalline solifenacin succinate
obtained in this
way was determined by laser diffraction. The result is shown in Fig. 6.
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..
,
Example 4: Production of solifenacin succinate in accordance with the inven-
tion
Crystalline solifenacin succinate with Bragg peaks at 3.7; 11.1; 18.6; 21.8
2 was
placed in a type MM 301 Retsch vibration grinding mill and ground with a ball
for
approx. 10 minutes at 15 Hz in a metal container intended for that apparatus.
The crystalline solifenacin succinate obtained in this way was examined under
a
light-optical microscope; the light-optical microscopic image is shown as Fig.
7. The
axial ratio found was approx. 1 : 1.
The particle size distribution of the crystalline solifenacin succinate
obtained in this
way was determined by laser diffraction. The result is shown in Fig. 8.
Comparative Example 1: Production of solifenacin succinate in accordance
with EP 1 714 965 Al
The crystalline solifenacin succinate was produced in accordance with Example
1 of
EP 1 714 965 Al, though because of the laboratory scale, the following amounts
of
solvents were used in the context of the recrystallisation, which were reduced
pro-
portionately to the amounts specified in the Example:
0.24 g solifenacin succinate were dissolved in 2.3 ml ethyl acetate and 0.45
ml etha-
nol and cooled to 0 C. The crystals had poor flow properties and had a
pronounced
tendency to agglomerate.
The crystalline solifenacin succinate obtained in this way was examined under
a
light-optical microscope; the light-optical microscopic image is shown as Fig.
9. The
axial ratio found was approx. 6: 1.
Comparative Example 2: Production of crystalline solifenacin succinate
100 mg crystalline solifenacin succinate with Bragg peaks at 3.7; 11.1; 18.6;
21.8 02
0 0.2 20 (manufacturer: Medichem S.A.) were heated in 8 ml ethyl acetate on
a
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2
water bath with backflow. The solution was chilled rapidly in an ice water
bath, and
the crystals were filtered off. The crystals had poor flow properties and had
a pro-
nounced tendency to agglomerate.
The crystalline solifenacin succinate obtained in this way was examined under
a
light-optical microscope; the light-optical microscopic image is shown as Fig.
10.
The axial ratio found was approx. 45 1.
Comparative Example 3: Production of crystalline solifenacin succinate
250 mg crystalline solifenacin succinate with Bragg peaks at 3.7; 11.1; 18.6;
21.8 2
0 0.2 2 (manufacturer Medichem S.A.) were heated in 8 ml ethyl acetate /
ace-
tone (1: 1) on a water bath with backflow. The solution was chilled rapidly in
an ice
water bath in an ultrasonic bath. The crystals were filtered off The crystals
had poor
flow properties.
The crystalline solifenacin succinate obtained in this way was examined under
a
light-optical microscope; the light-optical microscopic image is shown as Fig.
11.
The axial ratio found was approx. 10: 1.
Example 5: Production of a tablet containing solifenacin succinate in accor-
dance with the invention
A tablet with an active-agent content of 5 mg solifenacin succinate in
accordance
with the invention was produced as follows and had the following composition.
Production:
2.5 kg solifenacin succinate in accordance with the present invention were
prepared
with 7.75 kg starch 1500, 25 kg Granulac 230 and 1.25 kg HPMC 606 in a
fluidised-
bed granulator (e.g. Glatt GPCG 30). 0.625 kg of the HPMC were sprayed on in
15
1 water (2.0 %). After the granules were dried, they were passed though a 1 mm
screen. 375 g magnesium stearate was passed though a 0.5 mm screen and added
to
the granules. The mixture was mixed in a barrel mixer for 10 minutes at 10
rpm. The
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tablet was compressed in a rotary press (e.g. ex Fette). The tablet was film-
coated
with an aqueous suspension of 1.2475 kg Opadry 11 and 2.5 g iron oxide yellow
in a
Glatt Coater 750. (Amount of water: 13.75 1)
Composition of the tablets:
solifenacin succinate 5.0 mg
starch 1500 15.5 mg
Granulac 230 50.0 mg
I-IPMC 606 3.75 mg
Mg stearate 0.75 mg
Opadry 11 2.495 mg
iron oxide yellow 0.005 mg
Example 6: Methods for characterising solifenacin succinate
The following methods were employed to characterise the solifenacin succinate
of
the kind which is the subject of the Examples and Comparative Examples
described
herein, unless any statements are made to the contrary. These methods can also
be
employed to determine the parameters, or the corresponding values,
characterising
the solifenacin succinate of the invention.
Production of X-ray powder diffractograms
The X-ray powder diffractograms were produced on a Panalytical X'Pert Pro
Series
(manufacturer: Panalytical). The equipment settings were as follows:
geometry: Bragg Brentano
copper cathode
range of angles 3 - 450 2 O.
The samples were measured by means of backloading methods or on zero-back-
ground holders. The measurements were performed with a Soller collimator 0.02
rad
using a nickel filter.
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Particle size analysis
In order to analyse particle sizes, 50 mg substance were typically moistened
with 5
drops of silicone oil in a test tube and suspended on a vortexer. 6 ml
silicone oil
were added and again suspended on a vortexer. The suspension was exposed to ul-
trasonic waves for 1 minute in an ultrasonic bath. After that a homogeneous
suspen-
sion was produced on the vortexer. Homogenisation was quite quickly successful
by
drawing the suspension into a pipette and emptying it again. After that,
enough sus-
pension was placed in the sample holding unit of a Mastersizer, using the
pipette,
until a shading of 10 - 25 % was obtained. The measurement was performed
without
any prior waiting time.
Light-optical microscopy
The microscope images were obtained on a Leica DMLB transmitted light micro-
scope. For this purpose, a spatula tip of substance was placed on a specimen
slide,
and 1-2 drops of paraffin oil were dripped onto it. Using a cover slip, a
uniform sus-
pension was produced on the specimen slide.
Determining the axial ratio
The average axial ratio was determined using the light-optical microscope
images by
establishing the extension in the longitudinal direction and the extension in
the trans-
verse direction, as described herein, wherein the value given corresponds to
the ave-
rage of the values measured for at least 10 crystals selected at random.
The features of the invention disclosed in the above description, claims and
draw-
ings can be essential to implementing the invention in its various embodiments
both
individually and in any combinations.
