Note: Descriptions are shown in the official language in which they were submitted.
CA 02329732 2000-10-20
WO 99/54048 PCT/GB99/01189
FUID ENERGY MILLING PROCESS AND APPARATUS
This invention is concerned with a process and apparatus for producing finely
divided
powders, especially of drug substances. In particular, the present invention
relates to
improvements in fluid energy milling.
Fluid energy milling, also known as micronising, is a procedure commonly used
for
producing finely divided powders. It is especially suitable for drug
substances because
there are no grinding media to contaminate the product. The reduction in
particle size in
the fluid energy mill is caused by attrition between the particles of the
substance being
milled, using energy imparted by compressed air.
The compressed air used in fluid energy milling has a very low humidity
because of the
increased potential for condensation in compressed air systems. Moisture is
removed
from the air after compression to avoid problems with condensation in
apparatus in which
the compressed air is used. It is customary to remove moisture by
condensation, by
cooling the compressed air after compression, and then to pass the compressed
air
through a desiccant tower before it is fed into a fluid energy mill.
Typically, the compressed air used in fluid energy milling has a pressure of
around 6 bar
and will have a dew point (at atmospheric pressure) below -40 °C, and
which may be as
low as -70 °C.
The process of micronisation may disrupt the crystal structure of substances
being
processed due to attrition during the milling. When milling crystalline
hydrates and
solvates the combination of attrition and very dry air may cause additiona!
damage, by
stripping water/solvate molecules from the crystal structure during
processing. After
milling the micronised material may be able to re-attain its original crystal
structure over
a period of time, depending on storage conditions. Therefore, a drug substance
which is a
crystalline hydrate may possibly not be at its original specification after
fluid energy
milling and may return to its original specification only after an
unpredictable length of
time in storage. In addition, the damage caused by attrition/desolvation may
affect the
intended properties of the product, for example, surface energy, stability,
bioavailability.
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WO 99154048 PCTIGB99101189
In a particular case, a milled powder agglomerated during further processing
rather than
dispersing uniformly.
The present invention is based on the discovery that controlling the humidity
of the
compressed air used in fluid energy milling in a range which is considerably
higher than
that generally used, but still below the humidity which would lead to
condensation
problems in the mill, results in less damage to the crystallinity in the
milled product.The
consequent reduction in or avoidance of desiccation of the substance during
the milling
processalso facilitates re-attainment of the original level of crystallinity
after milling.
Therefore, this invention provides micronised output that is more consistent
and with
improved control of quality attributes. This gives much reduced inter-batch
variation,
leading to less reworking or failure of batches. In addition, theprocess of
the invention
does not have a detrimental effect on the particle size reduction achieved by
the
micronisation process.
In its broadest aspect, the present invention provides a fluid energy milling
apparatus
including means for adjusting humidity of the compressed air used for milling.
The invention also provides a milling process which comprises feeding
compressed air
into a mill chamber containing particulate material and subjecting the
material to fluid
energy milling, characterised in that the humidity of the compressed air is
monitored and,
if necessary, the humidity is adj usted to reduce damage to the milled
product.
The adjustment made in accordance with this invention will typically be to
increase the
humidity. However, once the optimum value has been determined, and the
apparatus has
been set up to produce the desired increase in humidity of the compressed air
source, it
may be necessary to make adjustments during milling to correct humidity levels
up or
down in order to retain the optimum value.
A typical fluid energy milling system comprises a source of compressed air, a
desiccant
tower and a mill including a milling chamber and a collection device. The
collection
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WO 99/54048 PCT/GB99/01189
device may be a filter sock in the exit air stream or an expansion chamber in
which the
energy of the air stream is dissipated allowing milled material to settle out.
The humidity
of the process air in the mill may be increased by arranging that the
desiccant tower is by-
passed, so that the compressed air is fed directly from the source to the
mill. However,
the system is preferably made controllable by providing a by-pass loop around
the
desiccant tower and a control valve to split the air flow between the by-pass
loop and the
desiccant tower, and by which the relative proportions of compressed air
travelling
through the by-pass and the tower can be varied. By monitoring the humidity of
the air
entering the rizill, the amounts of air passing through the by-pass and
through the
desiccation tower can be adjusted using the control valve so as to achieve the
desired
humidity in the milling chamber.
In an alternative embodiment, undried air may be mixed with the dried air at a
particular
compressed air outlet in order to apply the humidity adjustment only to the
process air
supplying a particular piece of equipment.
In a further embodiment, humidity can be adjusted by injecting water,
preferably as a mist
or spray, into the compressed air-lines at an upstream location which allows
moisture to
be dispersed throughout the air stream before it reaches the mill.
The humidity is preferably assessed by measurement of dew point. The present
invention
includes any process in which the humidity is adjusted so that the process air
in the mill
has a dew point above the dew point of the compressed air as produced.
Typically the
humidity is increased to a dew point (at atmospheric pressure) of from -30
°C to 5 °C
preferably about -15 °C to 0 °C. Optimal values for specific
materials can be determined
by routine testing, varying the dew point and assessing product quality.
The humidity is typically measured by a dew-point hygrometer. The measurement
may
be made continuously, for example, by a sensor placed in the air stream prior
to entry into
the milling chamber; or intermittently, for example, by sampling the air in
the air stream
prior to entry into the milling chamber.
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WO 99/54048 PCT/GB99/01189
The present invention may be applied to any fluid-energy milling process, for
example in
a system in which an internal classifier releases particles as they reach a
pre-determined
size or in a system without a classifier in which product may be passed
through the mill
more than onceuntil all particles are within a desired size range.
An additional advantage of the present invention, in addition to its
beneficial effect on the
quality of the micronised output, is that it appears to improve the
micronisation process
itself, making maintenance of feed rate and balancing of air pressures more
easy.
Furthermore, the process of the invention improves the consistency and quality
of
micronised drug substance output demonstrated over a period of continued
production.
In addition, the present invention is particularly effective for the
preparation of finely
divided drug substance for use in a pharmaceutical composition. Accordingly,
in a
further aspect, the present invention provides for a pharmaceutical
composition
comprising a drug substance obtainable by a process as hereinbefore described.
The invention will improve the quality of micronised output for most
substances, but is of
particular applicability to the micronisation of substances susceptible to
crystal damage
during the process. Since removal of water of crystallinity (if present) in
itself can
destabilise a crystal structure, potential for crystal damage during
traditional
micronisation processing of crystalline hydrates is a serious problem, which
the invention
will overcome.
In a preferred embodiment, the procedures of the present invention are used in
the
preparation of micronised calcium mupirocin dihydrate (EP 0 167 856-A2,
Beecham
Group plc). Previously, fluid energy milling of this substance has produced
micronised
product that forms undesirable aggregates when compounded into an ointment
base. It
has been postulated that this is caused by surface energy changes resulting
from loss of
water of crystallisation and damage to the crystal structure by milling in
very dry air.
Controlling the humidity of the process air to an atmospheric pressure dew
point from
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WO 99/54048 PCT/GB99/01189
about -15 to about 0 °C has overcome this problem. Micronised calcium
mupirocin
dehydrate produced according to the procedures of this invention preferably
has a
moisture content of from 3.0 to 4.0, more preferably 3.4 to 3.7% and a low
amorphous
content, preferably 5% or less after recovery of crystallinity.
Accordingly, in a further aspect, the present invention provides for a
pharmaceutical
composition comprising micronised calcium mupirocin dehydrate obtainable by a
process
as hereinbefore described. Such compositions will benefit from containing drug
substance of more consistent quality attributes, avoiding, in an ointment, for
example,
formation of aggregates of calcium mupirocin dehydrate.
Preferred such compositions include ointments, creams and nasal sprays, such
as those
described in EP 0 231 621-A2 (Beecham Group plc), EP 0 251 434-A2 (Beecham
Group
plc), WO 95/10999 (SmithKline Beecham Corp) and WO 98/I4189 (SmithKline
I S Beecham). A preferred composition is an ointment comprising calcium
mupirocin
dehydrate in a white soft paraffin base containing a glycerine ester,
available as the
product Bactroban Nasal, from SmithKline Beecham. A further preferred
composition is
a cream comprising calcium mupirocin dehydrate in a base comprising mineral
oil,
polyethylene glycol (1000) monocetyl ether, cetyl alcohol, stearyl alcohol,
xanthan gum
and water, available as the product Bactroban Cream, from SmithKline Beecham.
This invention is illustrated by the following Examples.
CA 02329732 2000-10-20
H,0 9g1~04g PCTIGB99101189
Example 1
A commercial scale plant for micronising calcium-mupirocin dihydrate passes
compressed air through silica gel columns to a micronising mill. A loop by-
passing the
silica gel drying columns was installed in the process air feed to the mill.
The proportion
of the air by-passing the drying columns was varied using a valve, so that the
humidity of
the process air could be controlled.
A single batch of calcium mupirocin was taken and divided into three portions
to carry
out three separate micronisations performed. The first micronisation (sub-
batch A) was
undertaken using the processing air as routinely delivered by the plant
compressor. The
dew point of the air was -58 °C. Two further portions of the input
material were
micronised, one (sub-batch B) using air controlled to a dew point target of -
10 °C, one
(sub-batch C) to a dew point of 0 °C (the upper limit of humidity
obtainable in this plant).
Each run produced ca. 5kg of micronised product. In each case, the dew point
was
measured by sampling air upstream of the mill adjacent the air inlet, and
assessed as the
dew point at atmospheric pressure.
All three micronised sub-batches met the reQuired particle size
specifications. The
outputs were then assessed for crystallinity by solution calorimetry and the
moisture
contents measured by Karl Fischer analysis. The sub-batch A micronised at a
dew point
of -58 °C showed desiccation (Moisture Content: 3.1-3.2% w/w) and an
amorphous
content of ca. 15% (cf. 2% in the unmicronised dihydrate). Sub-batches B & C,
produced
at dew points of -10 °C and 0 °C respectively, showed no
desiccation (Moisture contents:
3.6% w/w) and had amorphous contents of ca. 9%. Continued monitoring of sub-
batches
showed that the amorphous content steadily decreased over the next few weeks
for the
sub=batches B & C, whereas, due to the desiccation, sub-batch A failed to
recover from
the crystal damage.
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WO 99154048 PCT/GB99101189
Sub-batches A and B were blended with an ointment base. The ointment made from
sub
batch A showed large numbers of aggregates; no aggregates were found in the
ointment
made from sub-batch B.
Example 2
In another experiment, the effect on moisture content and crystal damage
(amorphous
drug content) was compared for portions of a batch of calcium mupirocin when
microrused using air controlled in a dew point range of -15°C to -
5°Cwith air as
generally produced from the compressed air system, of dew point ca. -
50°C, whilst
varying other micronisation parameters to simulate stressing of the process.
The portions
of the batch micronised using controlled dew point air (-15°C to -
5°C) gave a mean
moisture content of 3.5% w/w and a mean amorphous drug content of 16.5%. The
portions of the batch micronised using standard compressed air {dew point ca. -
50°C)
gave a mean moisture content of 2.9% wlw and a mean amorphous drug content of
38.3%. When utilising the controlled humidity process, the output drug
substance was of
a much more consistent quality than with the generally produced compressed
air,
demonstrating that the invention improves the ruggedness of the micronisation
process.
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