Note: Descriptions are shown in the official language in which they were submitted.
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SOLVATE OF CABERGOLINE AND PREPARATIONS OF CABERGOLINE FORM I
FIELD OF THE INVENTION
[0001] The present application relates to the preparation of
cabergoline, in particular to a new process for preparing cabergoline Form I.
BACKGROUND OF THE INVENTION
[0002] Cabergoline is an ergoline derivative with formula 1-((6-
allylergolin-8j3-yI)-carbonyl)-1-(3-dimethylaminopropyl)-3-ethylurea. It is
known for
treatment of a number of diseases, including CNS disorders, reversible
obstructive airways disease, prolactin inhibition, for controlling intra-
ocular
pressure and for treating glaucoma.
[0003] A number of different forms of cabergoline are known and, by
way of example, PCT patent publication no. WO 01/72747 describes
cabergoline Form II and PCT patent publication no. WO 01/72746 describes
cabergoline Form VII.
[0004] Preparation of cabergoline Form I is described in PCT patent
publication nos. WO 01/70740, WO 03/078392 and WO 03/078433. For
example, PCT patent publication no. WO 01/70740 teaches the preparation of
crystalline cabergoline Form I from a solvent comprising a
toluene/diethylether
mixture whereas PCT patent publication nos. WO 03/078392 and WO 03/078433
teach crystalline cabergoline Form I that is obtained by drying a solvate of
cabergoline and toluene.
[0005] Pending U.K. patent application no. GB 0409785.3 teaches
a process for preparing cabergoline Form I of high yield and purity and with
desirable particle size distribution using ethylbenzene optionally in
conjunction with an anti-solvent such as n-heptane. GB 0409785.3
further describes a cabergoline ethylbenzene solvate.
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[0006] A series of cabergoline polymorphs are also described in
PCT patent publication no. WO 2004/101510.
[0007] It is desired in the present invention to prepare crystalline
cabergoline Form I having high purity. It is also desired to prepare
cabergoline having a particle size (following crystallization) which is
relatively
small and which requires no or relatively little milling to obtain the
particle size
desired in the eventual pharmaceutical product. Milling and other such
processing is undesirable as it tends to lead to conversion of pure
polymorphic
forms of cabergoline into polymorphic mixtures. One problem with the
methods described in PCT patent publication no. WO 03/078433, for
example, is that crystals of cabergoline Form I obtained have a relatively
large particle size.
[0008] It is also desired to provide a process for preparation of
cabergoline in which conversion of an intermediate solvate to the final
cabergoline Form I product is quick and efficient. A difficulty with known
processes for this conversion is that protracted drying periods are required
to
remove the solvent from the solvate - in excess of 48 hours - for the methods
set forth in PCT patent publication no. WO 03/078433.
SUMMARY OF THE INVENTION
[0009] One aspect of the present invention provides a method
for preparing cabergoline Form I comprising dissolving cabergoline in a p-
disubstituted benzene of formula (A)
x
(A)
~
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where X is a halogen, and Y is selected from the group consisting of a
halogen or a C2 to C5 linear alkyl, and recovering the cabergoline Form I
polymorph from the solution in the p-disubstituted benzene, suitably by
direct crystallization or recovery of a solvate which can be converted into
cabergoline Form I.
BRIEF DESCRIPTION OF THE DRAWINGS
[00010] Figure 1 is an X-ray powder diffraction pattern for the
cabergoline Form I obtained using 4-fluorotoluene as solvent (Example 1);
[00011] Figure 2 is a 13C CPMAS spectrum of cabergoline Form I
obtained using 4-fluorotoluene as solvent (Example 1);
[00012] Figure 3 is an X-ray powder diffraction pattern of
cabergoline Form I obtained using 1-chloro-4-fluorotoluene as solvent
(Example 4);
[00013] Figure 4 is a differential scanning calorimetry (DSC)
trace of damp cabergoline Form I obtained using 1-chloro-4-fluorobenzene
as solvent (Example 4);
[00014] Figure 5 is a differential scanning calorimetry (DSC)
trace of dry cabergoline Form I obtained using 1-chloro-4-fluorobenzene as
solvent (Example 4);
[00015] Figure 6 is an FTIR scan of cabergoline Form I obtained using
1-chloro-4-fluorobenzene as solvent (Example 4);
[00016] Figure 7 is a 13C CPMAS spectrum of cabergoline Form I
obtained using 1-chloro-4-fluorobenzene as solvent (Example 4);
[00017] Figure 8 is an X-ray powder diffraction pattern of
cabergoline Form I obtained using 1,4-difluorobenzene as solvent (Example
6); and
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[00018] Figure 9 is a!3C CPMAS spectrum of cabergoline Form I
obtained using 1,4-difluorobenzene as solvent (Example 6).
DETAILED DESCRIPTION OF THE INVENTION
[00019] The present invention involves preparing cabergoline Form I
by dissolving cabergoline in a p-disubstituted benzene of formula (A),
x
(A)
Y
where X is a halogen, and Y is selected from the group consisting of halogens
preferably bromine or iodine, more preferably bromine, or C2 to C5 alkyl,
preferably C2 to C4 alkyl and still more preferably C2 or C3 alkyl, to form a
solution, and then recovering the cabergoline Form I polymorph. Cabergoline
Form I can be recovered from the solution, suitably by direct crystallization
to
obtain cabergoline Form I or by recovery of a solvate which can be converted
into cabergoline Form I.
[00020] Preferably, the p-disubstituted benzene of formula (A) is
substituted with fluorine at the X position. More preferably, the p-
disubstituted benzene of formula (A) is substituted with fluorine at the X
position and where Y is selected from the group consisting of C2 to C5 linear
alkyl, preferably C2 to C4 alkyl and still more preferably C2 or C3 alkyl, or
halo,
preferably bromine.
[00021] In one preferred embodiment of the invention, cabergoline
Form I may be obtained by forming a solvate of cabergoline and a p-
disubstituted benzene of formula (A), optionally further comprising an anti-
solvent (for example heptane), and obtaining cabergoline Form I from this
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solvate. Cabergoline Form I may be obtained from the solvate by either direct
crystallization of Form I, or recovery of a solvate which can be converted to
Form
[00022] In another embodiment of the present invention,
cabergoline Form I is prepared by dissolving cabergoline in a solvent
comprising a p-disubstituted benzene of formula (A), optionally adding an anti-
solvent (for example heptane) to form a solvate, and the solvate is dried to
obtain cabergoline Form I.
[00023] In another embodiment of the present invention, cabergoline
is dissolved in a solvent which comprises a p-disubstituted benzene of formula
(A) (and optionally 1,3,5-trimethylbenzene) and the solution is cooled to a
temperature of -5 C or below. The solvent preferably comprises at least 75%
by volume of a p-disubstituted benzene of formula (A). It is contemplated in
accordance with the present invention that the solvent may consist solely of a
p-disubstituted benzene of formula (A).
[00024] In a further embodiment of the present invention, cabergoline
is dissolved in a solvent selected from a p-disubstituted benzene of formula
(A)
(and optionally 1,3,5-trimethylbenzene). The dissolving process is optionally
performed at room temperature, typically about 25-30 C and the resulting
solution is preferably filtered to remove particulate material. The
temperature
of the solution is then lowered to about -17 C or below, preferably -23 C or
below, thereby forming a precipitate of cabergoline. Formation of the
cabergoline precipitate can optionally be encouraged by stirring or seeding
using crystalline cabergoline Form I.
[00025] To the cabergoline precipitate an anti-solvent is added. As
used herein, an anti-solvent is generally a liquid in which cabergoline,
and/or
cabergoline/p-disubstituted benzene of formula (A) solvate is highly
insoluble.
The anti-solvent preferably comprises hexane, heptane, diethylether,
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diisopropylether, tertiarybutylmethyl ether or mixtures of these solvents. The
anti-solvent more preferably comprises heptane, and most preferably comprises
n-heptane.
[00026] The addition of the anti-solvent results in formation and
precipitation of cabergoline, or a cabergoline/p-disubstituted benzene of
formula
(A) solvate, forming a slurry that can be filtered to recover a solid, which
is
optionally washed, for example with further anti-solvent, and then dried to
yield
cabergoline Form I having high purity.
[00027] The ratio of the first solvent, i.e., the solvent comprising a p-
disubstituted benzene of formula (A) to the second solvent, i.e., the anti-
solvent, is
generally in the range of 4-10:5-20 volumes, preferably in the range of 5-7:8-
15
volumes and more preferably in the range of 5-7:10-12 volumes. It is most
preferable that the ratio of the first solvent to the second solvent is
approximately
5-6:11.
[00028] Advantageously, wet solvate of the present invention
that can be recovered by filtration can be rapidly dried to form crystals of
cabergoline Form I.
[00029] Drying of the wet solvate can be achieved in a number of
different ways. For example, drying has been carried out under reduced
pressure, at pressures of 900 mbar or less, 800 mbar or less and 700 mbar or
less. In each of these examples, a dried, pure cabergoline Form I was obtained
within 30 hours. Drying can also be carried out at elevated temperatures. It
is
contemplated in accordance with the present invention that the wet solvate can
be
rapidly dried at 40 C to 60 C.
[00030] Yet another option is to dry the wet solvate in an inert gas
atmosphere. The inert gas atmosphere comprises nitrogen, argon and/or other
inert gases at a concentration of 80% or higher by volume. Preferably the
inert
gas atmosphere comprises 5% or less oxygen. In addition, a nitrogen or other
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inert gas blanket can be used to dry the wet solvate or drying can be carried
out in a stream of an inert gas. It has been found that drying using an inert
gas can be completed in less than approximately 20 hours. This is especially
an advantage when preparing cabergoline Form I at large scale.
[00031] The above methods have been found, advantageously, to
yield cabergoline Form I having a relatively small particle size, typically
with a
volume median diameter (VMD) of less than 90 microns. [Example 8 below
illustrates the particle size advantages associated with cabergoline Form I
prepared using solvents of the type presently claimed, for example, 4-
fluorotoluene, 1-chloro-4-fluorobenzene, and 1,4-difluorobenzene
respectively.] Any milling of the product after crystallization tends to
result in
loss of polymorph purity, and therefore this relatively small particle size is
a
significant advantage in preparation of a pharmaceutical product having
cabergoline Form I of high purity.
[00032] Also provided by the present invention is cabergoline Form 1,
obtained by the methods of the invention, and a solvate of cabergoline
comprising cabergoline and a p-disubstituted benzene of formula (A).
[00033] The following examples illustrate the invention without
intending to limit the scope of the invention.
EXAMPLES
Example I
Preparation of Cabergoline Form I using 4-fluorotoluene
[00034] 5.0 grams of cabergoline (purity 99.9% by HPLC percentage
peak area) was dissolved in 15 mL of a solvent (4-fluorotoluene) to form a
solution. The solution was cooled to -20 C to give a gel. After 7 hours, 110
mL of a pre-filtered solution of an anti-solvent (n-heptane), also at -20 C,
was
added dropwise over a 20-minute period.
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[00035] Once the addition was complete, the slurry was stirred at
-20 to -15 C for 3.5 hours. The product was then collected by filtration
under a
blanket of nitrogen and the filter cake washed with cold (-20 to -15 C) n-
heptane. The filter cake was then dried under a blanket of nitrogen for 30
minutes.
[00036] The resulting solid was then placed in a vacuum oven with
a nitrogen purge at 45-50 C. Full vacuum was then appiied to the solid in the
vacuum oven at 40 to 50 C until the sample was at constant weight.
[00037] Samples of the product were subjected to chromatographic
tests such as FTIR, DSC and X-ray crystallographic analysis (as set forth in
Figure 1) and determined to be pure cabergoline Form I. The yield was 96.7%.
Example 2
Preparation of Cabergoline Form I using 4-fluorotoluene
[00038] The procedure of Example 1 was repeated; except that 2.0
grams of cabergoline were dissolved in 10 mL of 4-fluorotoluene and 22 mL of n-
heptane were added in the subsequent stage.
[00039] Samples of the product were subjected to FTIR and determined
to be pure cabergoline Form I. DSC analysis of damp material showed a peak at
52.5 C and DSC analysis of dry material showed a peak at 104.20 C. The yield
was 77.8%.
Example 3
Preparation of Cabergoline Form I using 4-fluorotoluene
[00040] The procedure of Example 1 was repeated; except that 2.0
grams of cabergoline were dissolved in 6 mL of 4-fluorotoluene and 44 mL of n-
heptane were added in the subsequent stage.
[00041] Samples of the product were subjected to FTIR, DSC
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and X-ray crystallographic analysis and determined to be pure cabergoline Form
1. DSC analysis of damp material showed a peak at 52.5 C and DSC analysis of
dry material showed a peak at 104.16 C. The yield was 82%.
Example 4
Preparation of Cabergoline Form I using 1-chloro-4-fluorobenzene
[00042] 2.0 grams of cabergoline was dissolved in 8 mL of solvent (1-
chloro-4-fluorobenzene) by warming to form a solution. The solution was then
filtered through a 0.45p filter which was then washed with 2 mL of 1-chloro-4-
fluorobenzene. The solution was then stirred in a freezer at -15 to -20 C for
20
hours. 44 mL of cold n-heptane was added in over 20 minutes.
[00043] Once the addition was complete, the suspension was stirred
at -15 to -20 C for 3.5 hours. The product was then collected by filtration
and
the filtrate was washed with cold heptane. The filtrate was then dried under a
blanket of nitrogen for 30 minutes, yielding 2.3 g (damp weight) of product
(DSC = 67 C).
[00044] The resulting solid was then subjected to a nitrogen
flow at 40 C followed by drying in vacuo at 40 C for 24 hours (DSC = 67 C)
and then drying the dried solid in vacuo at 50 C for an additional 96 hours
(DSC = 103.1 C).
[00045] Samples of the product at both drying stages were
subjected to chromatographic tests such as FTIR, DSC and '3C CPMAS
analysis (as set forth in Figures 3-7) and determined to be pure cabergoline
Form I.
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Example 5
Preparation of Cabergoline Form I using I-chloro-4-
fluorobenzene
[00046] 2.25 grams of cabergoline was dissolved in 6.75 mL of
solvent (1-chloro-4-fluorobenzene) at 19.5 C to form yellow homogenous
solution. The solution was then polish filtered and the filter was washed with
2.25 mL of 1-chloro-4-fluorobenzene. The solution was then stirred in a
freezer at -15 to -17 C until a white solid precipitated without seeding. 49.5
mL
of cold n-heptane was added (at -20 to -25 C) under a blanket of nitrogen over
a period of 15 minutes. The flask containing the mixture was returned to the
freezer and stirred overnight.
[00047] The solid was then filtered off the next day and washed with
cold filtrate (mother liquor) to help transfer the solid. The filtered solid
was
then kept under suction and a positive stream of nitrogen for 20 minutes and
then transferred to a hot (40 C) oven with nitrogen for 3 hours. The damp
weight was 2.69g.
[00048] The solid was then dried in an oven in vacuo at 45 C
overnight to yield 2.113g of dry solid.
[00049] Samples of the product were subjected to DSC analysis
resulting in the following results and confirming that the product formed was
pure cabergoline Form I.
Very Small Peak Main Peak
Integral -3.23 mJ -126.69 mJ
Onset 62.62 C 95.45 C
Peak 65.50 C 102.20 C
Endset 68.17 C 104.84 C
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Example 6
Preparation of Cabergoline Form I using 1,4-difluorobenzene
[00050] 2.0 grams of cabergoline was dissolved in 6 mL of
solvent (1,4-difluorobenzene) at 18 C. The solution was then polish filtered
and
the filter was washed with I mL of 1,4-difiuorobenzene. The solution was then
kept in a freezer at -17 C with no stirring. No precipitate formed and the
solution
was seeded with cabergoline Form I and left overnight at -17 C in a freezer
with
no stirring. 44 mL of cold n-heptane was added in over a period of 15 minutes.
The flask containing the mixture was returned to the freezer to stand
overnight
-17 C with no stirring.
[00051] The next day the solid was filtered and washed with cold filtrate
(mother liquor) to help transfer the solid. The filtered solid was then kept
under
suction and a positive stream of nitrogen for 20 minutes and then transferred
to a
hot (40 C) oven with nitrogen for 3 hours. The damp weight was 2.203g. The
solid was then dried in an oven in vacuo at 45 C for 24 hours to yield 1.82g
of dry
solid.
[00052] Samples of the product were subjected to FTIR analysis
resulting in a determination that the product formed was pure cabergoline Form
I.
Example 7
Preparation of Cabergoline Form I using 1,3,5-trimethylbenzene
[00053] The procedure of Example 1 was repeated using 1,3,5-
trimethylbenzene (mesitylene) as the solvent. Specifically, 2.0 grams of
cabergoline was dissolved in 50 mL of 1,3,5-trimethylebenzene and the
resulting solution, was processed as described in Example 1.
[00054] Analysis of the resulting product showed that it consisted
predominantly of cabergoline Form I, together with a minor amount (3.8%) of
the Form II.
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Example 8
Comparison of Polymorphs Obtained from Different Solvents.
[00055] The procedure of Example 4 was repeated using the solvents
indicated in the following table. The polymorphic form obtained is indicated
in the
right hand column.
Solvent Polymorphic form
1 -chloro-4-fluorobenzene/heptane Form I
4-methylanisole Form II
chlorobenzene/heptane A mixture of polymorphic forms.
Fluorobenzene/heptane A new polymorphic form according to
DSC, X-ray and SS13C analysis
(designated Form FB)
Comparison of Particle Size of Cabergoline Polymorphs Obtained from
Different Solvents.
[00056] The procedure of Example I was repeated using 4-
fluorotoluene/heptane, 1,3,5-trimethylbenzene, 1-chloro-4-
fluorobenzene/heptane, and 1,4-difluorobenzene respectively. The particle
size of the cabergoline Form I polymorph obtained in each instance was
measured and compared to the particle size of cabergoline Form I obtained
according to WO 03/078433, disclosing the preparation from toluene/heptane
and to the particle size of cabergoline Form II. The results are shown in the
Table below.
Polymorph; Solvent Xio X50 X90 VMD
iam pm pm pm
Form I 1.76 106.21 158.01 84.95
4-fluorotoluene/heptane
Form I 2,96 45.01 141.84 61.80
1,3,5-trimethylbenzene
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Form I 9.17 28.42 69.74 34.02
1,chloro-4-fluorobenzene
Form 1 24.35 42.83 77.64 47.54
1 ,4-difluorobenzene
Form I 36.67 100.05 149.69 96.01
Toluene / heptane
Form li 46.68 117.56 159.36 111.26
[00057] Accordingly, the present invention provides methods for
obtaining crystalline cabergoline Form I with high purity, which is easy to
dry
from the intermediate solvate and which has a particle size that facilitates
preparation of a pharmaceutical product with reduced post-crystallization
processing.
[00058] The use of the terms "a" and "an" and "the" and similar
references in the context of describing the invention (especially in the
context
of the following claims) are to be construed to cover both the singular and
the
plural, unless otherwise indicated herein or clearly contradicted by context.
The terms "comprising," "having," "including," and "containing" are to be
construed as open-ended terms (i.e., meaning "including, but not limited
to,") unless otherwise noted. Recitation of ranges of values herein are
merely intended to serve as a shorthand method of referring individually to
each separate value falling within the range, unless otherwise indicated
herein,
and each separate value is incorporated into the specification as if it were
individually recited herein. All methods described herein can be performed in
any suitable order unless otherwise indicated herein or otherwise clearly
contradicted by context. The use of any and all examples, or exemplary
language (e.g., "such as") provided herein, is intended merely to better
illuminate the invention and does not pose a limitation on the scope of the
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invention unless otherwise claimed. No language in the specification should
be construed as indicating any non-claimed element as essential to the
practice of the invention.
[00059] Preferred embodiments of this invention are described
herein, including the best mode known to the inventors for carrying out the
invention. Variations of those preferred embodiments may become apparent
to those of ordinary skill in the art upon reading the foregoing description.
The
inventors expect skilled artisans to employ such variations as appropriate,
and
the inventors intend for the invention to be practiced otherwise than as
specifically described herein. Accordingly, this invention includes all
modifications and equivalents of the subject matter recited in the claims
appended hereto as permitted by applicable law. Moreover, any combination of
the above-described elements in all possible variations thereof is encompassed
by the invention unless otherwise indicated herein or otherwise clearly
contradicted by context.
