Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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PROCESS FOR PREPARING CRYSTALLINE FORM I OF CABERGOLINE
This application claims priority to U.S. application Serial No. 60/364,567,
filed March
15, 2002, and U.S. application No. 60/410,253, filed September 12, 2002, the
entirety of
each of these applications are hereby incorporated by reference herein.
Cabergoline is an ergoline derivative interacting with D2 dopamine receptors
and is
endowed with different useful pharmaceutical activities and it is used in the
treatment of
hyperprolactinemia, central nervous system disorders (CNS) and other related
diseases.
to Cabergoline is the generic name of 1((6-allylergolin-8(3-yl)-carbonyl)-1-(3-
dimethylaminopropyl)-3-ethylurea, described and claimed in US 4,526,892. The
synthesis
of cabergoline molecule is reported also in Eur. J. Med. Chem., 24,421,(1989)
and in GB-
2,103,603-B.
Cabergoline Form I, like cabergoline, displays a significant inhibitory effect
with regard
15 prolactine and has therapeutic properties that make it possible to treat
patients who have
pathological conditions associated with an abnormal prolactine level, thus is
useful in
human and/or veterinary medicine. Cabergoline is also active, alone or in
combination, in
the treatment of reversible obstructive airways diseases, for controlling
infra-ocular pressure
and for the treatment of glaucoma. It is also employed in the veterinary
field, as
2o antiprolactin agent and in cutting down drastically the proliferation of
vertebrate animals.
The several uses of cabergoline are for example described in WO99/48484,
W099/36095,
US5705510, W095/05176, EP040,325.
Cabergoline Form I is particularly useful in the treatment of Parkinson's
disease (PD),
Restless Legs Syndrome (RLS), treatment of diseases like Progressive
Supranuclear Palsy
25 (PSP) and Multysystemic atrophy (MSA).
Crystalline cabergoline Form I, an anhydrous not solvated form of cabergoline,
was firstly
prepared by crystallization from diethyl ether, as described in Il Farmaco, 50
(3), 175-178
(1995).
Another process for preparing crystalline Form I of cabergoline through a
toluene solvate
3o Form V was described in WO01/70740.
For purposes of lowering the cost of the bulk, it is highly desirable to
improve the yield of
the industrial production of crystalline Form I of cabergoline and to avoid
lengthy process.
Therefore, it is an objective of the present invention to obtain a highly pure
Form I of
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cabergoline using an organic solvent system that has never been heretofore
used. Efficiently
preparing highly pure cabergoline in crystalline Form I provides benefits with
respect to
industrial costs and environmental considerations.
The present invention concerns a new process for preparing crystalline Form I
of
cabergoline.
The method of the present invention comprises the preparation of a new toluene
solvate of
cabergoline and its exclusive conversion into crystalline Form I of
cabergoline. The new
toluene solvate of cabergoline is a crystalline form fully characterized
herein below, but
it is referred to for convenience as "Form X".
In another aspect, the invention provides solvated crystalline Form X of
cabergoline that,
when de-solvated, can quickly and exclusively yield crystalline Form I of
cabergoline.
In a fourth aspect, the invention provides processes for preparing solvated
crystalline
Fonn X of cabergoline and a process for preparing crystalline Form I of
cabergoline from
solvated crystalline Form X of cabergoline.
FIG. 1 is an x-ray powder diffraction (XRD) pattern showing peaks
characteristic of
crystalline cabergoline solvate Form X, made in accordance with Example 1.
FIG. 2 is an x-ray powder diffraction (XRD) pattern showing peaks
characteristic of
crystalline cabergoline Form I, according to Example 2.
FIG. 3 is an x-ray powder diffraction (XRD) pattern showing peak
characteristic of the
original toluene solvate, referred to as Form V made in accordance with
procedure outlined
in WO01/70740:
FIG. 4 is a differential scanning calorimeter (DSC) profile of Form X, showing
thermal
event associated with eutectic melting of cabergoline with toluene.
FIG. S is a differential scanning calorimeter (DSC) profile of Form V, showing
thermal
event associated with eutectic melting of cabergoline with toluene
FIG. 6 is the time resolved powder x-ray data of the de-solvation phase
transformation of
Form X at 43° C under high vacuum (94.8 kPa).
According to the present invention, Form I can be readily prepared starting
from crude
material by crystallization from a toluene/heptane or toluene/hexane mixture,
through a
3o new solvate Form X of cabergoline. The present process for preparing Form I
shows
advantages with respect to the old ones because of the rapid and exclusive
conversion of
solvate Form X of cabergoline into Form I. The new solvate Form X of
cabergoline, a
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novel gel-mediated process for its preparation and a process for its
conversion into
crystalline cabergoline Form I are also~provided.
Characterisation
X-ray powder diffraction (XRD) was used to characterise the new solvate Form X
of
cabergoline and compare it to Forms I and V. The de-solvation and phase
conversion of
form X to form I was studied by studying the solvate in a special cell on the
X-ray
diffractometer at elevated temperatures under high vacuum over a period of
time.
Differential scanning calorimeter (DSC) profiles were also obtained for Forms
V and X to
show the distinct nature of these solvates.
X-ray diffraction analysis
Powder X-ray diffraction was performed using either a Siemens D5000 powder
diffractometer or an Inel multipurpose diffractometer. For the Siemens D5000
powder
diffractometer, the raw data were measured for 2~ (two theta) values from 2 to
50, with
steps of 0.020 and step periods of two seconds. For the Inel multi-purpose
diffractometer,
samples were placed in an aluminium sample holder and raw data were collected
for one
thousand seconds at all 26values simultaneously. The data so obtained are
shown in the
tables I to III herein below.
A special cell that could be heated and evacuated through a vacuum pump was
used to study
the de-solvation and phase conversion behaviour of Form X to Form I on the
Inel multi-
purpose diffractometer. The de-solvation and phase conversion behaviour of
Form X to
Form I was studied at
43° C and 94.8 kPa vacuum. The very high vapour pressure of toluene
necessitated high
vacuum for efficient solvent removal. For the de-solvation and phase
conversion of Form X
to Form I, the Inel multi-purpose diffractometer was programmed to collect X-
ray
diffraction data for ten minutes every half an hour for a total
experimentation time of two
hours and forty minutes (including data collection).
The x-ray powder diffraction pattern for solvate Form X (Figure 1) shows a
crystalline
structure with useful distinctive peaks as depicted in the following table I.
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Table I X-Ray diffraction data, Form X
Angle ~ Intensity Intensity
26 Cps X 1000
7.988 6899 100.00
10.937 837 11.97
12.067 477 6.82
14.927 2213 31.66
17.162 2603 37.25
17.320 3163 45.26
19.938 855 12.22
21.075 2720 38.92
23.892 1371 19.61
26.779 1086 15.54
The x-ray powder diffraction pattern for cabergoline Form I (Figure 2) shows a
crystalline
structure with distinctive peaks depicted in the following table II.
Table II X-Ray diffraction data, Form I
Angle Intensity Intensity
28 Cps X 1000
9.870 4458 99.86
10.497 1498 33.55
12.193 1244 27.86
14.707 1556 34.86
16.658 1743 39.94
16.721 1644 36.83
18.707 4464 100.00
20.822 2330 52.19
22.688 1172 26.25
24.652 2341 52.44
The x-ray powder diffraction pattern for the known toluene solvate Form V of
cabergoline
(Figure 3) described in WO01/70740 has a crystalline structure with
distinctive peals
depicted in the following table III
1o Table III X-Ray diffraction data, Form V
Angle Intensity Intensity
20 Cps X 1000
8.866 5930 100.00
12.287 705 11.88
16.375 1440 24.28
18.171 1169 19.71
18.991 1167 19.67
21.043 1214 20.47
24.93 8 751 12.66
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These data clearly indicate that cabergoline Form X is a new crystalline
polymorph solvate
easily distinguishable by XRD from tha known solvate V described in the prior
art.
The de-solvation and phase transformation behaviour of Form X to Form I under
the
aforementioned conditions (Figure 6), shows that most of Form X, which is
characterised
by its main peak at 7.988 degrees 2 0 had transformed to Form I (characterised
by 9.870 and
18.707 degrees 2 8 peaks) within thirty minutes. The transform was complete
within one
hour as indicated by the complete disappearance of 7.988 degrees 2 B peak.
Figure 6 clearly shows the favourable kinetic of de-solvation and phase
transformation from
Form X to Form I. This data also demonstrates the very significant short time
for making
l0 Form I through' Form X.
Differential Scanning Calorimeter analysis (DSC).
Differential scanning calorimeter profiles were obtained from a Mettler-Toledo
822e
differential scanning calorimeter. The data was collected between 25 and
150° C at a
heating ramp of 10° C/min. Forty micro-liter hermetically sealed
aluminium pans with a
pinpricked hole in the lid were used.
Differential scanning calorimeter profile for Form X (Figure 4, shows a major
endothermic
thermal event centred around 53° C, followed by a minor and broad
endothermic thermal
event centred around 74° C. The former corresponds to eutectic melting
of Form X with
toluene, while the latter could be associated with the gradual loss of toluene
through
vaporization. For the purposes of this invention eutectic melting is defined
as the
transformation of solvent containing solids into a homogeneous liquid solution
without any
significant loss of solvent associated with the solids.
Differential scanning calorimeter profile for Form V (Figure 5) shows a single
endothermic
thermal event centred around 66° C. This thermal event corresponds to
the eutectic melting
of Form V in toluene.
Comparison of Figures 4 and 5 also shows the distinct nature of Forms X and V.
The process of the present invention for producing crystalline cabergoline
Form I is
characterized by crystallization from toluene/heptane. Hexane can also be used
instead of
heptane. Heptane is however, preferred for its toxicological properties, which
are better
suited for pharmaceutical application.
The process comprises dissolving cabergoline in a suitable amount of toluene,
preferably
in an amount of from 2.5 to 4.0 g of toluene per gram of cabergoline, more
preferably
about 3.5 g of toluene per gram of cabergoline, at room temperature.
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The cabergoline used as starting material can an oil obtained through the
synthesis
described in Eur. J. Med. Chem.,24, 421,~198~9), or can be any crystalline
form of
cabergoline or mixture thereof, including Form I crystals, obtained from the
procedures
described in the aforementioned references.
The resulting solution is cooled to temperatures below -10 °C and
stirred overnight,
preferably for a minimum of 18 hours.
During the overnight hold period the solution of cabergoline in toluene turns
into a gel,
which for the purposes of this invention is defined as a thick non-Newtonian
suspension
of bi-refringent solids in equilibrium with a saturated solution within the
suspension.
to Cold heptane or hexane, preferably around 10 to 20 g per gram of
cabergoline in the gel
phase, is then added to the gel. This addition of cold heptane or hexane is
termed as the
"quenching" of the gel phase. It refers to very strong anti-solvent properties
of heptane or
hexane for cabergoline toluene solutions. These properties essentially help
freeze a solid
suspension like the aforementioned gel, in a given solid state by eliminating
the driving
force for subsequent solid phase conversions to crystalline forms that may be
more stable
than Form X.
Upon the addition of heptane or hexane the gel turns into easily suspendable
slurry, which is
stirred at sub-ambient temperatures. Under these conditions, the toluene
solvate Form X is
obtained, that may be recovered by common procedures, for example by
filtration under
reduced pressure or by centrifugal filtration, followed by washing of the
solids with pure
heptane or hexane to remove residual mother liquor and free toluene. The
resulting crystals
of Form X are very unstable when removed from their mother liquor and
essentially convert
to Form I without applying any heat under ambient storage within twenty four
hours.
Form I crystals obtained in this particular manner, however, may contain
residual toluene at
levels unacceptable for pharmaceutical use and therefore preferably the solids
are heated in
a vacuum oven for lowering toluene content to within the acceptable range.
This drying
process can be accomplished by any suitable means such as, but not limited to,
heating the
solids, reducing the ambient pressure surrounding the solids, or combinations
thereof. The
drying pressure and time of drying are not narrowly critical. The drying
pressure preferably
3o is about 101 kPa or less. As the drying pressure is reduced, however, the
temperature at
which the drying can be carried out and/or the time of drying likewise is
reduced.
Particularly for solids wet with high boiling solvents like toluene, drying
under vacuum will
permit the use of lower drying temperatures. The optimum combination of
pressure and
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temperature is usually determined from the vapour pressure versus temperature
diagram for
toluene and operational factors related t~o the design of the dryer. The time
of drying need
only be sufficient to allow for the reduction in the level of toluene to a
pharmaceutically
acceptable level. When the solids are heated to remove the solvent, such as in
an oven, a
temperature that preferably does not exceed about 150°C is selected.
Alternatively, Form I cabergoline can be prepared directly from the solvated
crystalline
Form X obtained immediately after filtration through a combined de-solvation
and drying
step. Given the exceedingly fast kinetics of de-solvation and phase conversion
of Form X to
Form I, this combined operation can be conducted without requiring any
modifications to
to the schematics of the drying process described in the preceding paragraph.
The crystals of Form I of cabergoline prepared according to the process of the
present
invention have preferably a polymorph purity > 95%, more preferably >98% at
yields in
excess of 90% w/w, compared to about 60% for the route described in
WO01/70740.
Toluene solvate Form X is also obj ect of the present invention. The x-ray
powder
diffraction pattern for Form X (Figure 1) shows a crystalline structure. These
data indicate
that cabergoline solvate Form X is easily distinguishable by XRD and DSC. The
solvate X
of this invention is a true solvate having a fixed composition of about 0.5
toluene moles per
mole of cabergoline. The significant differences with the known hemi solvate
form
described in WO01/70740 can be readily appreciated looking at the respective
XRD and
DSC spectra.
The following Examples contain detailed descriptions of methods of preparation
of solid
state forms of cabergoline described herein. These detailed descriptions fall
within the scope
of the invention and illustrate the invention without in any way restricting
that scope. All
percentages are by weight unless otherwise indicated.
Example 1. Preparation of solvated crystalline Form X of cabergoline.
3 g of cabergoline were dissolved in 10.5 g of toluene in a 125 mL jacketed
reactor
equipped with an overhead agitation system. Once a clear solution had formed
under
agitation at 142 revolutions per minute, the reactor was cooled to a set point
of-18 °C in
order to achieve a temperature of-15 °C in the reactor. The solution
was stirred overnight
(a minimum of 18 hours). During this period it turned into a thick gel. In a
separate reactor
45 g of heptane were cooled to -15 °C and then transferred to the
reactor containing the gel
over a period of fifteen minutes. The resulting slurry was stirred at -15
°C for three and a
half hours before being discharged onto a filtration flask operating under
reduced pressure.
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The cake was washed with 6 mL of heptane to remove mother liquor and wash away
excess
toluene from the solids. These solids were'left of the filter for thirty
minutes.
They were identified as Form X by XRD, data shown in figure 1 and in table 1.
Yield was
about 102%(w/w) on the basis of initial content of pure "toluene free"
cabergoline.
Example 2. Preparation of crystalline Form I of cabergoline.
The crystal solvate Form X obtained in example 1 was placed in vacuum oven
under 94.8
kPa of vacuum at ambient temperature for two hours. The temperature was then
increased to
43 °C and the solids were fizrther dried for 24 hours. Another 24 hours
of drying was
afforded at
l0 60 °C. XRD and solvent content analysis on the solid samples pulled
after each phase of the
drying indicated that solids had converted to Form I after first phase of
drying (at ambient
temperature and high vacuum), however the toluene content was not within the
specifications on the product. The solids met all the product specifications
after the second
phase of drying (24 hours at 43 °C under high vacuum). After drying,
the resultant crystal
15 Form I was identified by XRD data shown in Figure 2. The overall yield was
about 93% on
the basis of pure cabergoline initial content. The assayed polymorph purity
was >98%.
