Note: Descriptions are shown in the official language in which they were submitted.
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PROCESS FOR PREPARING PRAMiPEXOLE DIHYDROCHLORI.DE
TABLETS
Field of the Invention
[00011 The present invention relates to a process for preparing tablets of
pramipexole
dihydrochloride. In particular, the present invention relates to a process for
preparing tablets of
pramipexole dihydrochloride wherein the tablets exhibit high storage stability
properties.
Background of the Invention
[00021 Pramipexole is a known dopamine D2 receptor agonist. It is structurally
different
from the ergot-derived drugs, e.g., bromocriptine or pergolide. It is also
pharmacologically unique in
that it is a full agonist and has receptor selectivity for the dopamine D2
family of dopamine receptors.
Pramipexole was originally disclosed in U.S. Patent Nos. 4,731,374, 4,843,086
and 4,886,812, all of
which are incorporated herein by reference.
[0003J Pramipexole is designated chemically as (S)-2-amino-4,5,6,7-tetrahydro-
6-
(propylamino)benzothiazole and has the molecular formula C,o.Hl7N3S and a
relative molecular mass
of 211.33. The chemical for.rnula is as follows:
N
i ~-NHz
V `N s
H
100041 The solvate form commonly used is pramipexole dihydrochloride
monohydrate
(molecular formula ClaH21C12N30S; relative molecular mass 302.27). Pramipexole
dihydrochloride
monohydrate is a white to ofF white, tasteless, crystalline powder. Melting
occurs in the range of
296 C to 301 C, with decomposition. Pramipexole is a chiral compound with
one chiral center.
The pure (S)-enantiomer is obtained from the synthetic process by chiral
recrystallization of one of
the intermediates during synthesis.
[00051 Pramipexole dihydrochloride monobydrate is a highly soluble compound.
Water
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solubility is more than 20 mg/mL and :solubility in buffer media is generally
above 10 mg/mL between
pH 2 and pH 7.4. Pramipexole dffiydrochloride monohydrate is not hygroscopic,
and has a highly
crystalline nature. Under milling, the crystal modification (monohydrate) does
not change.
Pramipexole is very stable in the solid state, yet in solution it is light
sensitive.
[0006] Pramipexole immediate release (IR) tablets were first authorized in the
USA in
1997, followed over the course of the next few years by marketing
authorizations in the European
Union (EU), Switzerland, Canada, and South America as well as in countries in
Eastern Europe, the
Near East, and Asia.
[00071 Pramipexole IR tablets are indicated in the EU and US for the treatment
of signs
and symptoms of either early Parkinson's Disease or advanced Parkinson's
Disease in combination
with Levodopa. The product is known in the USA under the brand name MIRAPEX ..
The IR tablets
are indicated to be taken 3 times a day.
100081 The manufacturing process for pramipexole dihydrochloride monohydrate
tablets,
which was marketed in the USA in 2005 (the marketed package/product
hereinafter referred to as the
"commercial formulation"), results in a tablet which has a relatively stable
shelf life wherein
approximately 95% of the labeled average amount of the active ingredient
remains in the tablet after
18 months of storage. However, it is desirable to develop products having as
close to zero
degradation as possible upon being stored for extended periods of time.
[0091 The present invention relates to a process for preparing tablets of
pramipexole
dihydr~ochloride monohydrate wherein the tablets exhibit high storage
stability properties.
Summary of the Cnvention
[00I0] For purposes of this disclosure and invention, hereinafter the tertn.
"pramipexole
dihydrochloride" means pramipexole dffiydrochloride and the pharmaceutically
acceptable solvates
thereof in particular including the monohydrate of pramipexole
dibydrochloride.
[00111 In accordance with the present invention, there is provided a process
for producing
tablets of pramipexole dihydrochloride wherein the tablets exhibit high
.storage stability properties.
{0012[ Furt.her provided is a process for preparing tablets of prarnipexole
dihydrochloride
wherein the process involves formulating tablets comprising intra-granular
tableting ingredients,
pramipexole dihydrochloride, a binder and extra-granular tableting agents. The
process comprises the
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steps of optionally sizing the intra-granular tableting ingredients to form
substantially uniform sized
particles of intra-granular tableting ingredients., forniing a premix
comprising the - optionally
substantiallyuniform.sized - intra-.granular tableting ingredients, the
pramipexole dihydrochloride and
the binder, granulating the premix and drying said granulated premix to an
endpoint moisture content
of from about 1.5% to about 2.5 /a, more preferably 1.0% to about 2.5% to form
a dried premix,
mixing the extra-granular tableting agents with the dried premix to form a
final blend and compressing
the final blend into tablets.
[0013] Further provided is a process for preparing pramipexole dihydrochloride
tablets
comprising intra-granular tableting ingredients, pramipexole dihydrochloride,
a binder and extra-
granular tableting agents, wherein at least a portion of the process is
performed in a closed system and
comprises the steps op
(a) loading particles of the intra-granular tableting ingredients into a fluid
bed granulator
wherein the particles of the intra-granular tableting ingredients may
optionally be sized prior
to loading to form substantially uniform sized particles and mixing the
ingredients,
(b) dissolving the pramipexole dihydrochloride and povidone in water to form
an aqueous
pramipexole dihydrochloride solution and spraying the pramipexole
dihydrochloride solution
onto the particles of intra-granular tableting ingredients in the fluid bed
granulator,
(c) preparing a binder paste and/or pasty suspension and/or suspension and
adding the binder
paste and/or pasty suspension and/or suspension to the fluid bed granulator by
spraying to
form a granulate,
(d) drying said granulated mix to an endpoint rnoisture content of from about
1.0% to about
2.5%,
(e) optionally pass the dried granulate through a screening mill to the raw
granulate
(f) mixing said granulated premix of step (e) with the extra-granular
tableting agents and
blending to form a fmal blend,
(g) compressing the final blend into tablets using a tablet .press.
[00141 In a preferred embodiment is provided a process for preparing
pramipexole
dihydrochloride tablets comprising intra- granular tableting ingredients,
pramipexole dffiydrochloride,
a binder and extra-granular tableting agents, wherein at least a portion of
the process is performed in
a closed system and comprises the steps of:
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(Step 1) loading mannitol, silica colloidal anhydrous and maize starch into a
fluid bed
granulator wherein the particles of the intra-granular tableting ingredients
may
optionally be sized prior to loading to forcn substantially uniform sized
particles and
mix the ingredients, preferably as a dry mixture,
(Step 2) dissolving the pramipexole dihydrochloride in water and povidone to
form an aqueous
pramipexole dihydrochloride solution and spraying the pramipexole
dihydrochloride
solution onto the particles of intra-granular tableting ingredients in the
fluid bed
granulator,
(Step 3) preparing.a paste of suspend maize starch in purified water and
adding the same to
the fluid bed granulator to form a granulate (Fluid Bed Granulation), while
preferably
protecting the wet granulate from light.
(Step 4) drying the granulate, preferably while protecting the dried granulate
from light.
(Step 5) preparing a raw granulate by a screening mill passing through the
dried granulate;
(Step 6) blending .the raw granulate with magnesium stearate, silica colloidal
anhydrous and
maize starch by means of a diffusion mixer (final blend).
(Step 7) pressing the final blend into tablets of the final strengths
(Tablets), e.g. about 210 mg.
(Step 8) optionally packaging.
[0015] The tablets produced in accordance with the aforementioned process and
embodiments thereof exhibit high storage stability attnbutes.
100161 A further aspect of the invention includes a process for the
manufacture of a
pharmaceutical tablet formulation comprising pramipexole dihydrochloride,
wherein the average
amount ofpramipexole dihydrochloride remaining.in the tablet at 18 months
under storage conditions
of 25 C and a relative humidity of 60% is at least about 97%of the labeled
amount.
100171 Another aspect of the invention includes a process for the manufacture
a
pharmaceutical tablet formulation comprising pramipexole dihydrochloride,
wherein the average
amount ofpraznipexole dihydrochloride remaining in the tablet at 24 months
under storage conditions
of 25 C and a relative hum.idity of 60% is at least about 95% of the labeled
amount and further may
be, preferably, at least about 97%.
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100181 Another aspect of the invention includes a process for the manufacture
a
pharmaceutical tablet formulation comprising pramipexole dihydrochloride,
wherein the average
amount ofp.ramipexole dihydrocliloride remaining in the tablet at 36 months
under storage conditions
of 25 C and a relative huniidity of 60% is at least about 95% of the labeled
amount and further may
be, preferably, at least about 97%.
[0019] The terrn "average amount" as used herein is calculated by determining
the amount
of the designated product (either active ingredient or degradation product)
present in a particular
sample of product and then taking an average of the samples of product.
100201 Usually in the final commercial pramipexole product, the tablets are
included .as
packaged products and packaging may include bottles, blister packs or the
like.
[00211 These and other features, benefits and advantages of the invention wilI
be apparent
from the following disclosure.
.Brief Description of the Drawings
100221 FIG. 1 is a flow chart showing a process for producing pramipexole
dihydrochloride tablets according to one aspect of the invention.
Detailed Description of the Invention
[0023] According to the present invention, pramipexole dihydrochloride tablets
can be
prepared which exhibit high storage stability. This is valuable in the
pharmaceutical arena as it
enables pharmaceutical manufacturers to produce and store the pramipexole
dibydrochloride tablets
for long periods thereby reducing concern as to whether the product has
exceeded its life and requires
disposal. This, in turn, eziables pharmacies, and ultimately consumers, to
enjoy the benefits of
reduced costs associated with the need to monitor the efficacy of a product
and the need to replenish
the market supply due to expiration of the product.
100241 In accordance with the invention, it has been found that by controlling
certain
parameters during the manufacture of pramipexole dihydrochloride tablets, the
resulting tablets
exhibit high stability. In particular, controlling the particle size ofintra-
granulartableting ingredients
so that they possess a relative substantial uniformity (optional), preparation
and use of a binder
suspension, performing the process in a closed system, as well as controlling
the moisture content of
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the product prior to tableting enables the production of a pramipexole
dihydrochloride tablet which
has highly desirable storage stability enhancements.
[0025] In accordance with the above, the pramipexole dihydrochloride tablets
of the
invention comprise intra-granular tableting ingredients, pramipexole dihydro
chloride, a binder and
extra-granular tableting agents. The process of the invention comprises the
steps of sizing the intra-
granular tableting ingredients to form substantially uniform sized particles
of intra-granular tableting
ingredients (optional step), forming a mix comprising the optionally uniformly
sized intra-granular
tableting ingredients, the pramipexole dihydrochloride and the binder,
granulating the mix and drying
said granulated mix to an endpoint moisture content (Loss on Drying (LOD) at
95 - 105 C,
preferably 105 C) of from about 1.0% to about 2.5% to form a dried mix, mixing
the extra-granular
tableting agents with the dried mix to form a final blend and compressing the
final blend into tablets.
In a further embodiment the granulated mix is dried to an end point moisture
content of from about
1.5% to about 2.5%.
[0026] A process for formulating the tablets whicb may result in commercial
pramipexole
products of high stability is set forth in Figure 1. The process shown in
Figure 1 involves a process
for preparing pramipexole dihydrochloride tablets comprising intra-granular
tableting ingredients,
pramipexoie dihydrochloride, a binder and extra-granular tableting agents,
wherein at least a portion
of the process is performed in a closed system. The process comprises the
steps of:
(a) loading particles of the intra-granular tableting ingredients into a fluid
bed granulator
wherein the particles of the intra-granular tableting ingredients may
optionally be sized prior
to loading to form substantially uniform sized particles,
(b) dissolving the pramipexole dihydrochloride and povidone in water to form
an aqueous
pramipexole dihydrochloride solution and spraying the prainipexole
dihydrochloride solution
onto the particles of intra-granular tableting ingredients in the fluid bed
granulator,
(c) preparing a binder paste and/or pasty suspension and/or suspension and
adding the binder
suspension to the fluid bed granulator by spraying,
(d) mixing the particles of intra-granular tableting ingredients, pramipexole
dihydrochloride
solution and binder solution in the fluid bed granulator to form a mix,
(e) granulating said mix to form a granulated mix,
(f) drying said granulated mix to an endpoint moisture content of from about
1.0% to about
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2.5%,
(g) mixing said granulated mix of step (f) with the extra-granular tableting
agents and
blending to form a final blend,
(h) compressing the final blend into tablets using a tablet press.
[0027] The intra-granular tableting ingredients include mannitol-D USP,
colloidal silicon
dioxide NF, povidone (K25) USP, corn starch NF and purified water USP.
[0028] The mannitol-D used as starting tnaterial .in the process of the
present invention
preferably is a mixture of the delta crystal modification and the beta crystal
modification. Preferably
the percentage in weight of the delta crystal modification exceeds the
percentage in weight ofthe beta
crystal modification. Preferably the percentage ofthe beta crystal
modification is not more than 10%,
with the remaining 90% being ofthe delta crystal modification. In one
embodiment, the beta content
is between 1.0 and 10%, preferably 1.5 and 10%, more preferably 2.0 and 10%
and even more
preferably 2.5 and 10%
[00291 The extra-granular tableting agents of the present invention include
colloidal
silicon dioxide NF, corn starch NF and magnesium stearate NF.
100301 With respect to the intra-granular tableting ingredients and extra
granular tableting
ingredients, the following table represents the preferred amounts oftableting
ingredients in each tablet
as a percentage of the overall amount used in each batch as well as the amount
of API (pramipexole
dihydrochloride):
Table 1
Ingredient % per batch
Mannitol-D 50-60
Corn Starch 35-45
Colloidal Silicon Dioxide 1-3
Povidone 1-3
Magnesium Stearate 1-3
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fAPI **
**The amount of API (pramipexole dihydrochloride) is dependent upon the
desired tablet strength.
[00311 Tablet strengths can be from 0.125 mg to 2.5 mg with typical strengths
being
0.125 mg, 0.25 mg, 0.50 mg, 0.75 mg, 1 mg, 1.5 mg and 2.0 mg.
[0032] The following table presents various tablet formulations which are
representative,
though not lirniting, examples of tablet formulations according to the
invention:
Table 2
Component mg/tablet
API 0.125 0.25 0.5 1.00 1.25 1.5
Mannitol 49.455 61.00 122.0 121.50 162.00 208.5
Corn starch, dried 25.010 30.90 61.8 61.85 82.55 106.0
Corn starch, undried 7.300 9.00 18.0 18.00 24.00 30.8
Colloidal Silicon Dioxide 0.940 1.20 2.4 2.30 3.10 4.0
Povidone (K25) 0.940 1.15 2.3 2.35 3.10 4.0
Magnesium Stearate 1..230 1.50 3.0 3.00 4.00 5.2
Purified Water * * * * * *
Tablet Weight 85.000 105.00 210.00 210.00 280.00 360.00
* For production, the purified water is adapted to the equipment used and does
not appear in the final
product.
j00331 The advantages to be realized from using the processes ofthe invention
to produce
the pramipexole dihydrochloride tablets of the invention include high storage
stability properties.
Such high storage stability properties include, but are not necessarily
limited to, high shelf life.
[00341 The high shelf life of the pramipexole dihydrochloride tablets prepared
according
to the processes of the present invention is exhibited by the ability of the
tablets to retain a high
percentage of active ingredient wben stored under certain conditions.
[0035] In particular, the pramipexole dihydrochloride tablets prepared
according to the
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process of the present invention has an average amount of pramipexole
dihydrochloride remaining in
the tablet at 18 months under storage conditions of 25 C and a relative
humidity of 60% of at least
about 97% of the labeled amount. The commercial formulation stored under the
same conditions
average less than 95.8% of the labeled amount (average amount). The trend for
the amount ofactive
ingredient present in the stored tablets prepared according to the invention
can be projected out to 24
and even 36 months where even at 36 months greater than 95 % of the labeled
amount should remain.
This of course is significant as it allows for long shelf life of the product
and thus cost savings to
consumers as the product does not have to be replaced by the manufacturer too
frequently due to
expiration of the unused product stored by the manufacturer, distributor
and/or pharmacist.
[00361 The following Example is representative of the process used to prepare
pram.ipexole dehydrate tablets according to the invention.
Example 2
[0037] The following process was used to prepare 0.5 mg tablets of pramipexole
dihydrochloride:
[0038] Into a fluid bed granulator, the following intra-granular ingredients
were dispensed
while passing through a comil (Quadro) having a 1.4 mm screen:
Mannitol-D: 122,000 g
Colloidal Silicon Dioxide: 1,200 g
Corn Starch, dried (undried): 56,000 (58,8) g
100391 In a separate stainless steel container, 500 g of .prazn.ipexole
dihydrochloride
monohydrate was dissolved in 20,000 ml of purified water with stirring and
then 2,300 g of
polyvidone 25 (Povidone K25 ) was added and dissolved to completion with
stirring. The
pramipexole dihydrochloride solution was then sprayed onto the mixture of
intra-granular ingredients
in the fluid bed granulator. In a separate stainless steel container, 5,800 g
of dried corn starch
(undried 6.09 g) was added to 15,000 ml of purified water with stirring
forming a starch paste. The
starch paste was then added to 38,000 ml of purified water which had been
heated to 95 C and
stirred at a rate of from about 350 RPM (stirring can be from about 250 RPM to
about 1250 RPM).
An additional 21,000 ml of purified water (room temperature) was then added
and stirred at 350
RPM. The temperature was allowed to cool to about 60 C (the temperature can
be from about 55
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C to about 65 C at this stage). The starch solution was then sprayed onto the
intra-granular
ingredients and pramipexole dihydrochloride mixture in the fluid bed
granulator. The material in the
fluid bed granulator was then granulated and dried .to a residual moisture
content of 2.3% and sieved
through a screening mill to form a pramipexole raw granulate. An extra-
granular blend of magnesium
stearate (3,000 g), colloidal silicon dioxide (1,200 g) and corn starch
(18,000 g) was mixed with
187,800 g of the pramipexole raw granulate in a diffusion mixer for 30 minutes
at 10 RPM to form a
final blend. The final blend was then compressed into tablets weighing 210 mg
and containing 0.5 mg
pramipexole dihydrochloride.
[0040] The present invention is not to be linaited in scope by the specific
embodiments
described herein, which are intended as single illustrations ofip.dividual
aspects of the invention, and
functionally equivalent methods and components are within the scope of the
invention. Indeed,
various modifications of the invention, in addition to those shown and
described herein will become
apparent to those skilled in the art from the foregoing description and
accompanying drawings. Such
modifications are intended to fall within the scope of the appended claims.
