Process for the preparation of fluticasone propionate form 1
The present invention relates to a novel crystallisation process for preparing fluticasone
propionate as crystalline form 1 polymorph with controlled particle size and suitable for
micronisation.
Fluticasone propionate is a corticosteroid acting as a potent anti-inflammatory and which is
used as crystalline form 1 in the treatment of rhinitis, eczema, psoriasis, asthma and
COPD. It has the chemical name S-(fluoromethyl)-6a,9-difluoro-1 i p-17-dihydroxy-1 6 -
methyl-3-oxoandrosta-1 ,4-diene-17p-carbothioate, 17-propionate and the following
chemical structure:
Several processes for preparing fluticasone propionate, in particular as its stable crystalline
form 1, have been described in the literature. For example, WO 00/3881 1 discloses the
crystallisation of fluticasone propionate dissolved in acetone by mixing with water in the
presence of ultrasound radiation. WO 01/32125 discloses the crystallisation of fluticasone
propionate by admitting a stream of solution of fluticasone propionate in acetone and a
stream of water as anti-solvent tangentially into a cylindrical mixing chamber having an
axial outlet port such that said streams are intimately mixed through formation of a vortex.
However, these processes are not easily scalable and use complex apparatus and
technologies (such as use of ultrasound).
Other, more simple, crystallisation processes have also been proposed. For example, the
so-called crystalline form 1 of fluticasone propionate can be obtained by dissolving the
crude product as obtained in e.g. GB 2088877 in ethyl acetate and then re-crystallising.
Alternatively, a method for preparing fluticasone propionate as crystalline polymorphic form
1 by mixing a solution of fluticasone propionate in a non-solvating organic liquid solvent
such as methyl acetate, ethyl acetate or pentanone, with a non-solvating organic liquid
anti-solvent such as toluene, isooctane or hexane thereby causing fluticasone propionate
as crystalline form 1 to crystallise out of the solution has been described in WO 03/066653.
However, it has been found that these crystallisation processes do not offer control and
flexibility in terms of output particle size distribution for fluticasone propionate. Similar to the
majority of drugs intended for delivery to the lung, fluticasone propionate is usually
subjected to micronisation prior to formulation to enable production of appropriately sized
respirable particles. It is however well known from the literature that there is a link between
the particle size of ingoing material and the size of micronized product, hence it is of key
importance to precisely control the particle size of the material that is fed into the
microniser to ensure reliable and effective drug delivery to the lung.
The present invention represents a solution to the above mentioned problems. The present
invention is indeed directed to a new crystallisation process for preparing fluticasone
propionate as crystalline form 1 which is scalable, reproducible and does not involve
complex apparatus. The crystallisation process according to the present invention also
enables more flexibility and precise control of product particle size distribution through
variations in solvent composition. Finally the crystallisation process according to the
present invention shows lower product loss in the micronisation chamber compared to a
traditional anti-solvent crystallisation.
The present invention is thus directed to a process for preparing fluticasone propionate as
crystalline form 1, which comprises the step of dissolving fluticasone propionate in acetone
or in a mixture of acetone and water and then adding this solution to water or to a mixture
of water and acetone, thereby causing fluticasone propionate to crystallise out of the
solution as crystalline form 1.
According to the present invention, the water or water/acetone mixture in which the
fluticasone propionate solution is added may also be referred as the "non-solvent" or the
"non-solvating mixture" respectively.
According to an embodiment, fluticasone propionate is dissolved in acetone containing 0 to
10% water, and the resulting solution is added to water containing 0 to 35% acetone.
Preferably, fluticasone propionate is dissolved in acetone, and the resulting solution is
added to water containing 0 to 30 % acetone.
According to another embodiment, a solution is prepared through dissolving fluticasone
propionate in acetone or an acetone/water mixture with concentrations between 30 and 50
grams per litre of solvent. Preferably, said solution is prepared through dissolving
fluticasone propionate in acetone or an acetone/water mixture with concentrations between
35 and 45 grams per litre of solvent.
According to a further embodiment, fluticasone propionate is dissolved in 1 volume of
acetone or acetone/water mixture and this solution is then added to a volume of water or
water/acetone mixture comprised between 0.65 and 1.35. Preferably, 1 volume of the
fluticasone propionate solution is added to a volume of water or water/acetone mixture
comprised between 0.8 and 1.2. More preferably, 1 volume of the acetone/ fluticasone
propionate solution is added to a volume of water or water/acetone mixture of about 1.
According to another embodiment, the addition takes place at a temperature comprised
between 10°C and 40°C. Preferably, the addition takes place at ambient temperature.
According to another embodiment, the addition takes place over a period comprised
between 10 minutes and 6 hours. Preferably, the addition takes place over a period
comprised between 30 minutes and 2 hours. More preferably, the addition takes place over
a period of about 1 hour.
According to another embodiment, the addition of the fluticasone propionate solution
occurs via a pump in the form of pulsed aliquots.
During and following from the addition of the fluticasone propionate solution into the nonsolvent
or non-solvating mixture, nucleation and growth of fluticasone propionate occur.
Once the fluticasone propionate solution addition into the non-solvent or non-solvating
mixture is completed, the slurry formed is stirred over a period comprised between 0 and
12 hours, followed by filtration and drying. Preferably, the slurry is stirred over a period of
comprised between 1 hour and 10 hours. More preferably, the slurry is stirred over a period
comprised between 4 hours and 8 hours. Still more preferably, the slurry is stirred over a
period of about 1 hour.
The process according to the present invention is particularly advantageous since it allows
good flexibility and control of the physical properties of the fluticasone propionate obtained,
in particular the size and shape of the particles obtained. This is exemplified in Figure 1,
showing the dependence of particle size on solvent composition when fluticasone
propionate is crystallised using the process described in the present invention. Surprisingly,
it has been found that the specific reverse anti-solvent crystallization process according to
the present invention allows the crystallization of fluticasone propionate with different
particle sizes through variations in solvent composition and also delivers fluticasone
propionate particles which do not exhibit the agglomeration which is typical of conventional
anti-solvent crystallization, as described for example by Murnane et al. in Cryst. Growth
Des. 2008, 8, 2753-2764 and as illustrated in Figure 2.
In addition to influencing the efficacious delivery of intra-nasal and pulmonary drug
formulations, control of physical properties of fluticasone propionate is also important since
these properties influence bulk density, flow and downstream processing characteristics of
the product.
Typically, the process according to the present invention yields particles that are 5-200 mih
in length with a width of 3-30 mih . The fluticasone propionate particles obtained by the
process according to the present invention thus have the most appropriate design, in
particular for micronisation and formulation with lactose as a dry powder and administration
with a dry powder inhaler such as the device described in e.g. WO 2005/002654. The
particles of fluticasone propionate obtainable from the herein described crystallisation
process thus constitute another object of the present invention.
An additional and significant advantage of the particles resulting from the process
according to the present invention is the increased yield in micronized fluticasone
propionate due to lower loss of product in the jet milling chamber, compared to
micronisation input obtained from a conventional anti-solvent process
Fluticasone propionate may be prepared according to any of the processes known from the
literature such as e.g the process described in GB 2088877. Alternatively, fluticasone
propionate is also commercially available for a number of suppliers, e.g. Hovione, Sterling
or NewChem.
The particles of fluticasone propionate as obtained from the crystallisation process
according to the present invention may be micronized to a controlled size and formulated
with lactose so as to form a dry powder blend.
Fluticasone propionate as obtained from the process according to the present invention is
particularly suitable for micronisation and administration by inhalation from a dry powder
inhaler. Typically, it is administered in the form of a dry powder as a mixture with lactose.
To that effect, the particles of fluticasone propionate as obtained from the process
according to the present invention are micronized by jet miling, and subsequently blended
with lactose. The lactose used according to the present invention may be anhydrous or in
the form of the monohydrate. Preferably, a-lactose monohydrate is used. The blend thus
obtained is then suitable for filling into a dry powder inhaler.
The dosage unit is determined by a pre-filled capsule, blister or pocket or by a system that
uses a gravimetrically fed dosing chamber. Units in accordance with the invention are
typically arranged to administer a metered dose or "puff" containing from 50 to 500 mg of
fluticasone propionate as obtained from the process according to the present invention.
The overall daily dose will typically be in the range of 50 mg to 2 mg which may be
administered in a single dose or, more usually, as divided doses throughout the day.
The fluticasone propionate obtained from the process according to the present invention
may be administered alone or in combination with one or more other drugs. Suitable
examples of other therapeutic agents which may be used in combination with fluticasone
propionate include, but are by no means limited to b2 agonists, preferably long-acting b2
agonists, and M3 muscarinic antagonists, preferably long-acting M3 muscarinic
antagonists.
Examples of suitable b2 agonists include in particular salbutamol, terbutaline, bambuterol,
fenoterol, salmeterol, formoterol, tulobuterol and their salts. Preferably the 2 agonist is
selected from salmeterol or formoterol and their salts. More preferably, the b2 agonist is
salmeterol xinafoate.
Examples of suitable M3 muscarinic antagonists include in particular ipratropium,
oxitropium, tiotropium and their salts. Preferably the M3 muscarinic antagonist is tiotropium
bromide.
According to a preferred embodiment, fluticasone propionate as obtained from the process
according to the present invention is administered by inhalation as a dry powder either
alone or in combination with salmeterol xinafoate.
The figures and examples below further illustrate the present invention.
FIGURES
Figure 1/10: Effect of acetone % in the anti-solvent mixture on the volume median
diameter D[v, 0.5] for a reverse anti-solvent process.
Figure 2/10: Crystals of fluticasone propionate obtained from example 1.
Figure 3/10: Crystals of fluticasone propionate obtained from example 2.
Figure 4/10 : PXRD patterns for Example 2 product (top line) and reference fluticasone
propionate form 1 pattern for comparison (bottom line).
Figure 5/10: Crystals of fluticasone propionate obtained from example 3.
Figure 6/10 : PXRD pattern for example 3 product (top line) and reference fluticasone
propionate form 1 pattern for comparison (bottom line).
Figure 7/10: Crystals of fluticasone propionate obtained from example 4.
Figure 8/10 : PXRD pattern for example 4 product (top line) and reference fluticasone
propionate form 1 pattern for comparison (bottom line).
0 : Crystals of fluticasone propionate obtained from example b.
Figure 10/10: PXRD pattern for example 5 product (top line) and reference
fluticasone propionate form 1 pattern for comparison (bottom line).
EXAMPLES
Example 1: Re-crystallisation of fluticasone propionate using a standard antisolvent
process
1.0g of fluticasone propionate [S-(fluoromethyl)-6a,9-difluoro-1 1 -17-dihydroxy-1 6amethyl-
3-oxoandrosta-1 ,4-diene-1 7p-carbothioate, 17-propionate] obtained from a
commercial source was mixed with 25ml_ acetone. The mixture was heated to 40 C,
and then cooled to 20 C. 25ml_ water was added to the solution at approximatively
20 C. Crystallisation of the product was observed during the addition. The slurry was
filtered under vacuum, and the isolated solid was dried in an oven at 50 C under 0.9
bar vacuum, yielding fluticasone propionate Form 1. Crystals obtained from this
experiment are shown in Figure 2.
Example 2 : Re-crystallisation of fluticasone propionate using the reverse antisolvent
process of the present invention
7.5g of fluticasone propionate [S-(fluoromethyl)-6a,9-difluoro-1 1 -17-dihydroxy-1 6amethyl-
3-oxoandrosta-1 ,4-diene-1 7p-carbothioate, 17-propionate] obtained from a
commercial source was mixed with 225ml_ acetone. The mixture was heated to
40 C, and then cooled to 10 C. The chilled solution was added to a separate
agitated vessel containing 225ml_ water at 40 C over a period of 10 minutes.
Crystallisation of the product was observed during the addition. The mixture was
cooled down to 20 C and held at that temperature for 12 hours. The slurry was
filtered under vacuum, and the isolated solid was dried in an oven at 50 C under 0.9
bar vacuum, yielding 6.94g of fluticasone propionate 30 (92.4% theoretical yield).
Crystals obtained from this experiment are shown in Figure 3.
Powder X-Rav Diffraction Data
The powder X-ray diffraction pattern was determined using a Bruker-AXS Ltd. D4 powder
X-ray diffractometer fitted with an automatic sample changer, a theta-theta goniometer,
automatic beam divergence slit, and a PSD Vantec-1 detector. The sample was prepared
for analysis by mounting on a low background cavity silicon wafer specimen mount. The
peaks obtained were aligned against a silicon reference standard. The specimen was
rotated whilst being irradiated with copper K-alpha1 X-rays (wavelength = 1.5406
Angstroms) with the X-ray tube operated at 40kV/35mA. The analyses were performed
with the goniometer running in continuous mode set for a 0.2 second count per 0.01 8° step
over a two theta range of 2° to 55°. Characteristic diffraction angles for the two known
polymorphs of fluticaseon propionate, as reported in EU Patent EP 0 937 100 B 1, are as
indicated below in table 1:
TABLE 1
A PXRD pattern of the product obtained from this experiment, shown to match that of form
1 for fluticasone propionate, is shown in Figure 4.
Example 3 : Re-crystallisation of fluticasone propionate using the reverse antisolvent
process of the present invention
10g of fluticasone propionate [S-(fluoromethyl)-6a,9-difluoro-1 1b-17-di hydroxy- 16a-methyl -
3-oxoandrosta-1 ,4-diene-17p-carbothioate, 17-propionate] obtained from a commercial
source was mixed with 200mL acetone. The mixture was heated to 40°C, and then cooled
to 10°C. The chilled solution was added to a separate agitated vessel containing 200mL
water at 10°C over a period of 10 minutes. Crystallisation of the product was observed
during the addition. The mixture was heated to 20°C and held at that temperature for 12
hours. The slurry was filtered under vacuum, and the isolated solid was dried in an oven at
50°C under 0.9 bar vacuum, yielding 9.33g of fluticasone propionate (93.3% theoretical
yield).
Crystals obtained from this experiment are shown in Figure 5.
A PXRD pattern from the product, shown to match that of form 1 for fluticasone propionate,
is shown in Figure 6.
Example 4 : Re-crystallisation of fluticasone propionate using the reverse antisolvent
process of the present invention
9g of fluticasone propionate [S-(fluoromethyl)-6a,9-difluoro-1 i p-17-dihydroxy-16a-methyl-
3-oxoandrosta-1 ,4-diene-17p-carbothioate, 17-propionate] obtained from a commercial
source was mixed with 270ml_ acetone. The mixture was heated to 40°C, and then cooled
to 10°C. The chilled solution was added to a separate agitated vessel containing 175ml_
water and 75ml_ acetone at 10°C over a period of 6 hours. Crystallisation of the product
was observed during the addition. The mixture was heated to 20°C and held at that
temperature for 12 hours. The slurry was filtered under vacuum, and the isolated solid was
dried in an oven at 50°C under 0.9 bar vacuum, yielding 8.56g of fluticasone propionate
(95.1 % theoretical yield).
Crystals obtained from this experiment are shown in Figure 7.
A PXRD pattern from the product, shown to match that of form 1 for fluticasone propionate,
is shown in Figure 8.
Example 5 : Re-crystallisation of fluticasone propionate using the reverse antisolvent
process of the present invention
9g of fluticasone propionate [S-(fluoromethyl)-6a,9-difluoro-1 i p-17-dihydroxy-16a-methyl-
3-oxoandrosta-1 ,4-diene-17p-carbothioate, 17-propionate] obtained from a commercial
source was mixed with 162ml_ acetone and 18ml_ water. The mixture was heated to 40°C,
and then cooled to 10°C. The chilled solution was added to a separate agitated vessel
containing 270ml_ water at 10°C over a period of 6 hours. Crystallisation of the product was
observed during the addition. The mixture was heated to 20°C and filtered under vacuum.
i solid was dried in an oven at 50 C under 0.9 bar vacuum, yielding .b ot
fluticasone propionate (84.0% theoretical yield).
Crystals obtained from this experiment are shown in Figure 9.
A PXRD pattern from the product, shown to match that of form 1 for fluticasone
propionate, is shown in Figure 10.
Example 6 : Re-crystallisation of fluticasone propionate using the reverse antisolvent
process of the present invention
0.958Kg of fluticasone propionate [S-(fluoromethyl)-6a,9-difluoro-1 1b- 17-dihydroxy-
16a-methyl-3-oxoandrosta-1 ,4-diene-1 7p-carbothioate, 17-propionate] obtained from
a commercial source was mixed with 24.7L acetone. The mixture was heated to 35 C,
and then cooled to 20 C. The solution was added to a separate agitated vessel
containing 24L water at 20 C over a period of 2 hours. Crystallisation of the product
was observed during the addition. The mixture was held at 20 C for 1 hour with
agitation. The slurry was filtered under vacuum, and the isolated solid was dried in an
oven at 75 C under 0.9 bar vacuum, yielding 0.85Kg of fluticasone propionate (88.3%
theoretical yield).
Example 7 : Re-crystallisation of fluticasone propionate using the reverse
antisolvent process of the present invention
2.50Kg of fluticasone propionate [S-(fluoromethyl)-6a,9-difluoro-1 1b- 17-dihydroxy-
16a- 25 methyl-3-oxoandrosta-1 ,4-diene-1 7p-carbothioate, 17-propionate] obtained
from a commercial source was mixed with 62.5L acetone. The mixture was heated to
35 C, and then cooled to 20 C. The solution was added to a separate agitated vessel
containing 47L water and 15.5L acetone at 20 C over a period of 2 hours.
Crystallisation of the product was observed during the addition. The mixture was held
at 20 C for 1 hour with agitation. The slurry was filtered under vacuum, and the
isolated solid was dried in an oven at 75 C under 0.9 bar vacuum, yielding 2.26Kg of
fluticasone propionate (90.4% theoretical yield).
Example 8 : Re-crystallisation of fluticasone propionate using the reverse antisolvent
process of the present invention
9.5Kg of fluticasone propionate [S-(fluoromethyl)-6a,9-difluoro-1 1b-17-di hydroxy- 16amethyl-
3-oxoandrosta-1 ,4-diene-17p-carbothioate, 17-propionate] obtained from a
commercial source was mixed with 237.5L acetone. The mixture was heated to 35°C, and
then cooled to 20°C. The solution was added to a separate agitated vessel containing
237.5L water at 20°C over a period of 4 hours. Crystallisation of the product was observed
during the addition. The mixture was held at 20°C for 4 hours with agitation. The slurry was
filtered under vacuum, and the isolated solid was dried in an agitated dryer at 75°C under
0.9 bar vacuum, yielding 8.5Kg of fluticasone propionate (89.2% theoretical yield).
Example 9 : Re-crystallisation of fluticasone propionate using the reverse antisolvent
process of the present invention
2.50Kg of fluticasone propionate [S-(fluoromethyl)-6a,9-difluoro-1 i p-17-dihydroxy-16amethyl-
3-oxoandrosta-1 ,4-diene-17p-carbothioate, 17-propionate] obtained from a
commercial source was mixed with 56.25L acetone and 6.25L water. The mixture was
heated to 35°C, and then cooled to 20°C. The solution was added to a separate agitated
vessel containing 40.6L water and 2 1.9L acetone at 20°C over a period of 1 hour.
Crystallisation of the product was observed during the addition. The mixture was held at
20°C for 1 hour with agitation. The slurry was filtered under vacuum, and the isolated solid
was dried in an oven at 75°C under 0.9 bar vacuum, yielding 2.15Kg of fluticasone
propionate (86.0% theoretical yield).
Example 10: Particle size data as measured by laser diffraction
The following particle size assays for crystallised and micronized fluticasone propionate
were used in this experiment:
Particle size method for recrystallised FP:
The particle size distribution was measured on the Malvern Mastersizer 2000 laser
diffraction system equipped with a Hydro 2000S liquid dispersion unit and flow cell. The
sample was prepared by adding 15 drops of Tween 80 to crystallised fluticasone
propionate within the glass 4 dram vial and mixing into a paste using a spatula, until all of
the powder is wetted out and a smooth, uniform paste is achieved. Then the paste is
added to the Hydro 2000S containing dispersant (0.1 % Tween 80 in deionised water) using
a spatula. When the obscuration target is achieved (20% ± 5%) the sample is left to stir
within the Hydro 2000S for 1 minute to allow the particles to wet out, disperse and ensure a
stable obscuration is achieved. Measurement is initiated after 1 minute of stirring.
Particle size method for micronised FP:
The particle size distribution was measured on the Sympatec HELOS laser diffraction
system (with R 1 optical module giving a measuring range of 0.1 / 0.18 - 35 mih) together
with SUCELL dispersing module. 100 mg of micronised sample is weighed into a 4-dram
vial and 15 drops (approximately 0.5 ml_) of Tween 80 is added from a 3ml wide-tipped
pipette to the powder. The mixture is then carefully stirred into a paste until all the particles
are wetted out and a uniform smooth mixture is achieved. Then the paste is added to the
SUCELL containing dispersant (0.025% Tween 80 in deionised water) using a spatula.
Once the optical concentration target is achieved (10-15%) then a measurement is taken.
The particle size data expressed as D[v, 0.1], D[v, 0.5] and D[v, 0.9] obtained from
examples 2-9 are summarized below in Table 2. D[v, 0.1], D[v, 0.5] and D[v, 0.9] represent
the 10th percentile volume diameter; 50th percentile volume diameter; and 90th percentile
volume diameter respectively. In general the n h percentile volume diameter is defined so
that n% of the particles have a volume equivalent particle diameter smaller than or equal to
the n h percentile diameter. In the case of D[v, 0.5], it coincides with the median value.
TABLE 2
Example 6 2.0 5.3 12.4
Example 7 3.4 11.4 32.1
Example 8 1.3 2.8 5.6
Example 9 6.2 22.5 53.4
This experiment shows that the particle size distribution varies through variations in solvent
composition.
Example 11: particle size data before and after micronisation
Particles were micronized using a JetPharma MC150 (6 inch spiral jet mill) using the
following conditions:
- Feed rate: 15 g/min
- Mill pressure: 3.5 bar
- Venturi Pressure: 5.5 bar
- Micronisation scale: 0.5 Kg.
The micronisation comparison of Examples 8 and 9 showing the impact of ingoing particle
size on micronisation output is summarized in Table 3 below:
TABLE 3
Example 12: product recovery after micronisation
An additional and significant advantage of the particles resulting from the process
according to the present invention is the increased yield in micronized fluticasone
propionate due to lower loss of product in the jet milling chamber, compared to
micronisation input obtained from a conventional anti-solvent process such as the one
described in Example 1. Several batches crystallised by either conventional anti-solvent
techniques (as described in Example 1) or reverse anti-solvent techniques according to the
present invention (as described Examples 2-9) were micronized, and the results
summarised on Table 4 below show that the percentage of product collected after
micronisation was on average much higher for reverse anti-solvent product batches than
for conventional anti-solvent ones. Additionally, a much lower portion of product was left in
the mill chamber if the product had originated from reverse anti-solvent.
TABLE 4 : Summary of product recovery after micronisation for
anti-solvent and reverse anti-solvent batches.
What is claimed is:
1. A process for preparing fluticasone propionate as crystalline polymorphic form 1
characterized in that it comprises the step of dissolving fluticasone propionate in a
solvent to form a solution, and then adding the solution to a non-solvent, thereby
causing fluticasone propionate to crystallise out of the solution as crystalline form 1;
wherein the solvent comprises acetone and from 0% to 10% water, based on the
volume of the solvent; and
wherein the non-solvent comprises water and from 0% to 35% acetone, based
on the volume of the non-solvent.
2. A process according to claim 1, wherein fluticasone propionate is dissolved in the
solvent in an amount between 30 and 50 grams per litre of solvent.
3. A process according to claim 1, wherein fluticasone propionate is dissolved in a first
defined volume of the solvent to form a solution, and the solution is then added to a
second defined volume of the non-solvent;
a ratio of the first defined volume to the second defined volume being between
1:0.65 and 1: 1 .35.
4. A process according to claim 2, wherein fluticasone propionate is dissolved in a first
defined volume of the solvent to form a solution, and the solution is then added to a
second defined volume of the non-solvent;
a ratio of the first defined volume to the second defined volume being between
1:0.65 and 1: 1 .35.
5. A process according to claim 1, claim 2, claim 3, or claim 4, wherein said adding the
solution takes place at a temperature between about 10°C and about 40 °C.
6. A process according to claim 1, claim 2, claim 3, or claim 4, wherein said adding the
solution takes place over a period of between about 10 minutes and about 6 hours.
7. A process according to claim 5, wherein said adding the solution takes place over a
period of between about 10 minutes and about 6 hours.
8. A process according to claim 1, claim 2, claim 3, or claim 4, wherein said adding the
solution occurs via a pump in the form of pulsed aliquots.
9. A process according to claim 1, claim 2, claim 3, or claim 4, wherein said adding the
solution occurs over a period of between about 10 minutes and about 6 hours via a
pump in the form of pulsed aliquots.
10. A process according to claim 1, claim 2, claim 3, or claim 4 , wherein once the step
of adding the solution to the non-solvent is completed, a slurry forms and the slurry is
stirred over a period of between 0 and about 12 hours, followed by filtration of the slurry
to recover fluticasone propionate as crystalline form 1 and drying of the recovered
fluticasone propionate.
11. A process according to claim 5, wherein once the step of adding the solution to the
non-solvent is completed, a slurry forms and the slurry is stirred over a period of
between 0 and about 12 hours, followed by filtration of the slurry to recover fluticasone
propionate as crystalline form 1 and drying of the recovered fluticasone propionate.
12. A process according to 7, wherein once the step of adding the solution to the nonsolvent
is completed, a slurry forms and the slurry is stirred over a period of between 0
and about 12 hours, followed by filtration of the slurry to recover fluticasone propionate
as crystalline form 1 and drying of the recovered fluticasone propionate.
13. A process according to claim 8, wherein once the step of adding the solution to the
non-solvent is completed, a slurry forms and the slurry is stirred over a period of
between 0 and about 12 hours, followed by filtration of the slurry to recover fluticasone
propionate as crystalline form 1 and drying of the recovered fluticasone propionate.
14. Fluticasone propionate form 1, wherein said fluticasone propionate form 1 is
obtained by a process according to according to claim 1, claim 2, claim 3, or claim 4,
wherein said fluticasone propionate form 1 has a median particle size of between
5 microns and 35 microns.
15. Fluticasone propionate form 1, wherein said fluticasone propionate form 1 is
obtained in the form of particles by a process according to according to claim 1, claim 2,
claim 3, or claim 4,
wherein said particles do not exhibit agglomeration.
16. Fluticasone propionate form 1, wherein said fluticasone propionate form 1 is
obtained in the form of particles by a process according to according to claim 1, claim 2,
claim 3, or claim 4,
wherein said particles are between 5 and 200 microns in length, and have a
width of between 3 and 30 microns.
AMENDED CLAIMS
received by the International Bureau on 12 DEC 201 2 ( 12.1 2.201 2)
1. A process for preparing fluticasone propionate as crystalline polymorphic
form 1 characterized in that it comprises the step of dissolving fluticasone
propionate in a solvent to form a solution, and then adding the solution to a
water-containing non-solvent, thereby causing fluticasone propionate to
crystallise out of the solution as crystalline form 1;
wherein the solvent comprises acetone and from 0% to 10% water,
based on the volume of the solvent; and
wherein the non-solvent comprises water and from 0% to 35%
acetone, based on the volume of the non-solvent.
2. A process according to claim 1, wherein fluticasone propionate is dissolved
in the solvent in an amount between 30 and 50 grams per litre of solvent.
3. A process according to claim 1, wherein fluticasone propionate is dissolved
in a first defined volume of the solvent to form a solution, and the solution is
then added to a second defined volume of the non-solvent;
a ratio of the first defined volume to the second defined volume being
between 1:0.65 and 1: .35.
4 . A process according to claim 2, wherein fluticasone propionate is dissolved
in a first defined volume of the solvent to form a solution, and the solution is
then added to a second defined volume of the non-solvent;
a ratio of the first defined volume to the second defined volume being
between 1:0.65 and about 1: 1 .35.
5. A process according to claim 1, claim 2, claim 3 , or claim 4 , wherein said
adding the solution takes place at a temperature between about 10°C and
about 40°C.
6. A process according to claim 1, claim 2, claim 3 , or claim 4 , wherein said
adding the solution takes place over a period of between about 10 minutes
and about 6 hours.
7. A process according to claim 5, wherein said adding the solution takes
place over a period of between about 10 minutes and about 6 hours.
8. A process according to claim 1, claim 2, claim 3 , or claim 4 , wherein said
adding the solution occurs via a pump in the form of pulsed aliquots.
9. A process according to claim 1, claim 2, claim 3 , or claim 4 , wherein said
adding the solution occurs over a period of between about 10 minutes and
about 6 hours via a pump in the form of pulsed aliquots.
10. A process according to claim 1, claim 2, claim 3, or claim 4 , wherein once
the step of adding the solution to the non-solvent is completed, a slurry forms
and the slurry is stirred over a period of between 0 and about 12 hours,
followed by filtration of the slurry to recover fluticasone propionate as
crystalline form 1 and drying of the recovered fluticasone propionate.
11. A process according to claim 5, wherein once the step of adding the
solution to the non-solvent is completed, a slurry forms and the slurry is stirred
over a period of between 0 and about 12 hours, followed by filtration of the
slurry to recover fluticasone propionate as crystalline form 1 and drying of the
recovered fluticasone propionate.
12. A process according to 7, wherein once the step of adding the solution to
the non-solvent is completed, a slurry forms and the slurry is stirred over a
period of between 0 and about 12 hours, followed by filtration of the slurry to
recover fluticasone propionate as crystalline form 1 and drying of the
recovered fluticasone propionate.
13. A process according to claim 8, wherein once the step of adding the
solution to the non-solvent is completed, a slurry forms and the slurry is stirred
over a period of between 0 and about 12 hours, followed by filtration of the
slurry to recover fluticasone propionate as crystalline form 1 and drying of the
recovered fluticasone propionate.
14 . Fluticasone propionate form 1, wherein said fluticasone propionate form 1
is obtained by a process according to according to claim 1, claim 2, claim 3, or
claim 4 ,
wherein said fluticasone propionate form 1 has a median particle size
of between 5 microns and 35 microns.
15. Fluticasone propionate form 1, wherein said fluticasone propionate form 1
is obtained in the form of particles by a process according to according to
claim 1, claim 2, claim 3, or claim 4,
wherein said particles do not exhibit agglomeration.
16. Fluticasone propionate form 1, wherein said fluticasone propionate form 1
is obtained in the form of particles by a process according to according to
claim 1, claim 2, claim 3, or claim 4,
wherein said particles are between 5 and 200 microns in length, and
have a width of between 3 and 30 microns.
Statement under Article 19(l)
The Written Opinion asserts that the claimed subject matter is
obvious over Coote (US 2005/0222107) in view of Ferrie (WO 01/32125). It
is our opinion that claim 1 as amended is not obvious over Coote in view of
Ferrie. The Written Opinion asserts that Coote discloses a process for
preparing fluticasone propionate as crystalline polymorphic form 1,
"characterized in that it comprises the step of dissolving fluticasone
propionate in a solvent to form a solution, and then adding the solution to
a non-solvent (antisolvent), thereby causing fluticasone propionate to
crystallise out of the solution as crystalline form 1 (para [0027]) wherein
the solvent comprises acetone and water (para [0037]; [0043])." The
Written Opinion combines Coote with Ferrie, which teaches use of an
acetone/water system to isolate fluticasone propionate.
Claim 1 has been amended to recite use of acetone, optionally
containing water, and a water-containing non-solvent. The non-solvent
contains between 0% and 35% acetone. Coote in fact teaches away from
use of an acetone/water system, as recited in the current application.
Coote teaches use of two organic solvents. Specifically, Coote recites use of
"a solution of fluticasone propionate in a non-solvating organic liquid
solvent with a non-solvating organic liquid anti- solvent." Coote, claim 1.
Coote teaches away from using acetone in combination with water, stating
that:
The compound of formula (II) may advantageously be
isolated with higher efficiency than by means of prior art
processes. For example, the process for the preparation of
the compound of formula (II) disclosed in G. H. Phillips et
al (1994) J Med Chem 37, 3717-3729 involves the isolation
of the product from an acetone/water system. The product
so prepared is extremely difficult to filter. In contrast, the
compound of formula (II), when prepared in accordance
with the present invention, is far easier to filter.
Furthermore, the process of the present invention may
also offer improvements in purity.
Coote, Paragraph [0043], emphasis added. Accordingly, Coote teaches that
an acetone/water solvent mixture is a poor choice of solvent for
recrystallizmg fluticasone propionate. Therefore, there is no motivation to
combine Coote with a reference teaching an acetone/water system, such as
Ferrie.