Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
Boehringer Ingelheim Pharma KG Case 1/1301
CA 02476621 2004-08-17
D-552161ngelheim PCT-Text
80104pct.210
Inhalation powder containing the CGRP antagonist BIBN4096 and process for
the preparation thereof
The invention relates to an inhalation powder containing the CGRP antagonist 1-
[N2-
[3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-
piperidinyl]carbonyl]-D-
tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine [BIBN4096] of formula I in the
form of
spherically nanostructured microparticles which are stable in their amorphous
state
under normal conditions (T < 50°C, relative humidity < 75%) and a
process for the
1 o manufacture thereof by which the thermodynamically stable or stabilised
active
substance can be processed in its amorphous state in a single step to form
microparticles.
The spherically nanostructured microparticles according to the invention are
suitable
for the preparation of inhalation powders in which no other excipients or
additives
(carrier materials) are required in order to obtain a powder which can be
handled on
an industrial scale, which can be further processed directly and has excellent
properties in terms of dispersibility and is sufficiently easy to process with
regard to
its cohesive properties. In another aspect the invention relates to the
inhalation
2o powders which may be obtained using the process according to the invention.
Formula I:
B
OH
1~W'' B r
O ' O
N N N
/ ~ H II NON
N O O
~N
NH2
-2-
Prior art
BIBN4096 is a highly effective CGRP antagonist for the treatment of migraine,
which
cannot be administered orally using conventional preparations as the substance
has
s only limited bioavailability by oral route.
In the case of inhalation powders, inhalable powders which are packed into
suitable
capsules (inhalettes) are delivered into the lungs by means of powder
inhalers.
Alternatively, they may be inhaled by the use of suitable powdered inhalable
aerosols
o which may contain, for example, an HFC134a, HFC227 or mixture thereof as
propellant gas.
The microparticles of the pure active substance are administered through the
airways
to the surface of the lung, e.g. in the alveoli, by the inhalation process.
These
~5 particles settle on the surface and can only be absorbed in the body after
the
dissolution process by active and passive transporting processes.
Inhalation systems are known in the literature wherein the active substance is
present either as a micronised suspension in a suitable solvent system as the
carrier,
20 or in the form of a dry powder.
Usually, inhalation powders are prepared e.g. in the form of capsules for
inhalation
based on the general teaching as described in DE-A-179 22 07, using the
chemically
most stable form of the active substance. Pharmaceutical preparations prepared
by
2s mixing a finely divided medicament with a coarser carrier medium are
dispersed in an
air current by a so-called "powder flow method" using the suction mode of the
inhaler
as the main energy source.
A critical factor in multi-substance systems of this kind is the uniform
distribution of
3o the pharmaceutical composition in the powder mixture. Moreover, the carrier
results
in additional stress on the lungs as well as the occurrence of undesirable
interactions, which may lead to problems of compatibility.
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One significant aspect of the administration of the active substance by
inhalation is
that only particles of a specific aerodynamic size enter the target organ,
namely the
lungs. The particle size of these particles destined for the lungs (inhalable
fraction) is
in the submicron range. Such particles are conventionally produced by
micronisation
s (grinding in an air stream). As a result, such particles may often be of
complex
composition in terms of their crystal properties as a result of this
mechanical step.
Similarly, the geometric form of the particles of starting material also
determines the
morphological properties of the micronised material.
o Apart from the jet grinding process, the airstream grinding process being of
particular
significance, it is also possible to produce a suitable micronised product by
alternative methods. Suitable micronising processes for preparing
microparticles in
the submicron range include, for example, the precipitation method including
the
processes in which the active substance can be precipitated as a non-
crystalline
~5 (amorphous) solid by evaporating the solvent beyond its maximum solubility,
precipitation by means of supercritical gases, such as the RESS or PGSS
process (J.
Jung, M. Perrut: Particle Design Using Supercritical Fluids, J. Supercrit.
Fluids 20
(2001), 179-219), the GASR process (M.P. Gallager et al.: Gas Antisolvenf
Recrystallization, Am. Chem. Soc. (1989)), the PCA process (D.J. Dixon, K.P.
2o Johnston: Polymeric Materials Formed by Precipitation with compressed Fluid
Antisolvent, AIChE Journal (1993, Vol. 39(1 ), 127), freeze-drying, spray
drying or a
combination of several of the abovementioned processes.
It is known from the literature that lung-bound particles measuring between
0.5 Nm
25 and 10 Nm, preferably between 0.5 Nm and 6 Nm, can be produced by spray-
drying.
Industrially usable formulations can normally be prepared from spray-dried
particles
of this kind using the method mentioned above (DE-A-179 22 07) which have
sufficient dispersibility for medical use (inhalation) [Y.-F. Maa, P.-A.
Ngyuyen, J.D.
Andya, N. Dasovich, T.D. Sweeny, S.J. Shire, C.C. Hsu, Pharmaceutical
Research,
30 15, No. 5 (1998), 768-775; M.T. Vidgren, P.A. Vidgren, T.P. Paronen, Int.
J.
Pharmaceutics, 35 (1987), 139-144; R.W. Niven, F.D. Lott, A.Y. Ip, J.M.
Cribbs,
Pharmaceutical Research, 11, No. 8 (1994), 1101-1109].
_m..~ _... . .... ~ _ 4. .......w-
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In addition to these examples there are other methods of production , proposed
by
pharmaceutical companies in particular, based on spray-drying processes, which
describe special formulations for inhalation powders.
Apart from the requirements set out hereinbefore, it should generally be borne
in
mind that any change to the solid state of a pharmaceutical composition which
can
improve its physical and chemical stability as well as its technical qualities
provides a
considerable advantage over less stable forms of the same medicament.
o Statement of the problem
The complex objective of the present invention was primarily to provide a
bioavailable formulation for the highly effective CGRP antagonist BIBN4096.
The
formulation according to the invention should have a rapid onset of activity
for the
treatment of acute pain or, in the case of migraine, pain with a very sudden
onset.
This means that rapid absorption of the active substance and a fast rise in
the
plasma level must be ensured.
Description of the invention
A rapid onset of activity for the treatment of acute pain and for achieving a
high
plasma level of the salts of the active substance BIBN4096 within the shortest
possible time can best be achieved, apart from by intravenous administration,
via the
lungs as the receiving organ.
Within the scope of the present invention it has now, surprisingly, been found
that
BIBN4096 in the form of the active substance base may be made sufficiently
bioavailable by administering it by inhalation. It has been found that when
the active
substance is administered by inhalation in the form of spherically
nanostructured
3o microparticles a bioavailability of about 60% based on the fine fraction of
the
formulation (corresponding to FPD determined according to USP 24 Suppl. 2000)
can be achieved.
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The formulation according to the invention does not require the addition of
any carrier
materials.
A first object of the present invention is thus an inhalation powder
containing the
active substance base 1-[N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-
oxoquinazolin-3-
yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
[BIBN4096] of
formula I in the form of spherically nanostructured microparticles,
characterised in
that
(a) the particles have a specific surface area of between 1 m2/g and 25 m2/g,
preferably between 1 m2/g and 20 m2/g, most preferably between 3 m2/g and
10 m2/g,
(b) the characteristic value Q~5,ga IS between 50% and 100% and
(c) the parameter X5o is between 1 ~m and 6 pm.
These microparticles are characterised by special physical and physico-
chemical
properties which lead to improved pharmacological/pharmacokinetic properties
when
2o the substance is administered. The availability of the substance - both
quantitative,
based on the quantity of active substance administered, and also based on a
high
plasma level to be achieved as quickly as possible - is determined not only by
the
biochemical properties of the substance but also by physicochemical
properties. If a
solid is administered, as in the case of an inhalation powder, the parameters
of
absolute solubility in the ambient medium and also the speed of dissolution in
the
ambient medium as a function of the local concentration of the active
substance and
time should be taken into consideration in particular.
Optimum administration by inhalation must therefore take into account the fact
that
3o the particles of active substance form a finely divided coating over the
surface of the
lungs. The crucial factor here is that the active substance is changed in such
a way
that the microparticles to be inhaled have advantages in terms of their
particle-to-
particle interaction and their dispersion or aerodynamic properties which mean
that
on the one hand the particles are deposited quantitatively in the deeper parts
of the
. w_.~~~.. . ~."~..__
CA 02476621 2004-08-17
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lungs and on the other hand the maximum possible surface area of the lungs is
covered. Therefore, the physical-chemical properties of the microparticles to
be
inhaled are of major importance in inhalation powders.
s The particles produced according to the invention have high physical
stability. In
particular, the properties of the particles when used as an inhalation powder
enable a
high proportion of fine particles to be realised, technically determined, for
example,
by cascade impactor measurement (Andersen Cascade Impactor, according to USP
24 or Pharm. Eur. Suppl. 2000). Typically, the proportion of the particles
according to
o this method which are less than 5 Nm in size (aerodynamically) is greater
than 15%,
while in some cases fine fractions of more than 50% are achieved. Apart from
this
key parameter for inhalable substances, the powder is characterised in that it
can be
further processed by current technical processes. Powders produced in this way
are
characterised by the physicochemical parameters of particle size, e.g.
measured by
~5 laser diffraction, as well as specific surface, e.g. measured by multipoint
B.E.T.
measurement. For the characteristic value Q~5.a~ the particle size of powders
thus
produced is typically between 50% and 100%, and for the parameter X5o it is
between 1 Nm and 6 um. Particles which are produced by the above methods
typically have values for the specific surface of between 1 m2/g and 25 m2/g,
ideally
2o between 1 m2/g and 20 m2/g, most preferably between 3 m2/g and 10 m2/g.
Geometrically, particles produced by the above methods have particle shapes
which
may be described, depending on the test conditions, between the extremes of
"spherical shape", "spherical shape with cavity, optionally with hole",
"spherical
shape with inwardly shaped convexities ", as well as "collapsed hollow body ".
Under
25 the scanning electron microscope the surface of such particles is
substantially
nanostructured.
It has been found according to the invention that BIBN4096 in the form of the
free
base can surprisingly be changed morphologically by a spray drying process in
such
3o a way that a powder prepared in this way can be transferred directly into a
primary
packaging means without any further steps, specifically without the need to
mix it
with a coarser carrier material, and can be delivered from said packaging
means for
inhalation by means of a powder inhaler.
w..~~ . _ ... .~
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The manufacturing process may be controlled so that the particles are present
in a
suitable particle size, normally between 0.1 and 10 Nm, and these particles
have
surface characteristics such that they are easy to fluidise/disperse.
It has also been found that the particle morphology including the particle
size can be
critically controlled by the choice of process parameters and manufacturing
parameters. One surprising factor is that powders of this substance which have
been
micronised by "conventional" stream grinding processes and are present in a
o comparable particle size spectrum nevertheless differ fundamentally in their
morphology from particles produced according to this invention, in terms of
their
surface characteristics/particle-to-particle interactions. This is apparent
from the fact
that the quality parameter known as the "Fine Particle Fraction of Delivered
Dose"
(e.g. according to the method of determining the "Aerodynamic Particle Size
~5 Distribution" - USP 24 or Pharm. Eur. Suppl. 2000) is improved by a factor
10 or
more. As there is no need for a carrier material in the formulation either,
the absolute
dose of active substance actually available to the patient in a given total
amount of
powder administered is improved by a significantly higher factor.
2o The method of preparation according to the invention is characterised in
that the
active substance is suitably dissolved, sprayed and dried in a spray tower.
The
principle of spray-drying consists of breaking up a solution or suspension of
the
product which is to be dried into fine droplets and drying them with a hot gas
current.
The solid fraction remaining after the solvent has evaporated is separated off
from
25 the gas current by means of an inertia force separator (e.g. cyclone)
and/or by a filter
unit and collected. The microparticles thus produced are characterised by
special
values in terms of particle size, specific surface area and morphology.
Organic solvents or organic aqueous solvent mixtures have proved suitable as
3o solvents. Preferably, an alcoholic aqueous solvent system is used, more
preferably a
solvent mixture consisting of ethanol/methanol/water and
ethanol/propanol/water and
most preferably the solvent mixture of ethanol and water. The molar proportion
of
water in the solvent mixtures should range from 0.1 to 10 times the amount of
the
-.~.~.."_,.~...,~__... ~.... w
CA 02476621 2004-08-17
_g_
molar proportion of the alcohol components, preferably from 0.5 to 4 times the
amount.
The adjustment of the active substance concentration is intended primarily to
make
the process economical. However, limits are imposed on the active substance
s concentration which may be selected, these limits being set by the fact that
the
surface qualities of the particles can be optimised by a specific ratio
between the
droplet size and solids concentration. Normally, a concentration of between
0.5 and
20% by weight, preferably between 2 and 10 percent by weight, most preferably
between 3 and 8 percent by weight should be selected. The droplet size is a
critical
o parameter for the production of inhalable particles. Depending on the nozzle
used
the throughput of spray gas should be selected in conjunction with the
throughput of
solution so as to achieve the desired droplet size. As there are a number of
combinations of the parameters "nozzle - throughput of spray gas - throughput
of
solution" which result in a suitable droplet size, the process can sensibly be
defined
15 by the droplet size which is to be selected for the process. This may be
characterised
by the characteristic value X5o (median value = particle size/droplet size,
below which
50% of the quantity of particles are found, with regard to the volume
distribution of
the individual particlesldroplets), which should be in the range between 1.5
pm and
20 Nm, preferably between 1.5 Nm and 8 pm, as well as the characteristic value
2o Q~5.a> (corresponding to the quantity of particles below 5.8 pm , based on
the
distribution by volume of the particles), which should be between 10% and
100%,
preferably between 30% and 100%.
On an industrial scale this is achieved by using a suitable commercial nozzle,
e.g.
25 single- or multi-substance nozzles which exhibit these characteristics as a
function of
the nozzle parameters (e.g. speed of rotation in the case of rotary atomisers
or
applied pressure and the resulting mass flow of the atomising gas in the case
of two-
substance nozzles) as well as the spray rate (volumetric flow of "spray
solution").
Apart from the special conditions which have to be adhered to during the
actual
3o spraying process, in order to generate suitable droplets for the drying
process, it is
apparent that the surface characteristics of the particles may also be
positively or
deliberately influenced by the choice of the drying parameters. The critical
characteristics which impinge on the drying step are the inlet and outlet
temperature
of the drying gas and the volumetric flow of the drying gas passed through.
Care
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_g_
should be taken to ensure that the droplets of suitable size are passed
through the
drying chamber in such a way that the droplets and the dried particles do not
come
into contact, or only come into slight contact, with the wall of the spray
tower. This is
achieved by the use of nozzles with a corresponding spray cone, by a spray
tower of
suitable diameter and by the flow conditions in the apparatus. The starting
temperature must be adapted to the process so that the powder has a
sufficiently low
residual solvent content and thus a sufficient chemical and physical stability
is
achieved. This is ideally obtained if the starting temperature is maintained
in the
region of the boiling temperature or slightly above. By contrast, the inlet
temperature
0 of the drying gas must be selected so that in conjunction with the parameter
"volumetric flow of drying gas" and the spray rate, the drying is gentle
enough to
produce particles with suitable surface qualities.
A second object of the invention is thus a process for preparing the active
substance
~5 base BIBN4096 in the form of spherically nanostructured microparticles,
comprising
the steps of
a) dissolving the active substance B1BN4096 in an organic solvent or an
organic-
aqueous solvent mixture to prepare a solution of the active substance with an
2o active substance concentration of between 0.5 and 20 percent by weight,
preferably between 2 and 10 percent by weight, most preferably between 3
and 8 percent by weight,
b) spraying the resulting solution of active substance in the usual way so as
to
25 obtain a spray mist with a droplet size having the characteristic value X5o
in
the range from 1.5 to 20 Vim, preferably from 1.5 to 8 Vim, and Q~S.s~ between
10% and 100%, preferably between 30% and 100%,
c) drying the spray mist thus obtained by means of a drying gas, while
applying
3o the following parameters:
...~_ ~ ~..~w.-.n._.. __
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~ an inlet temperature of the drying gas of 100°C to 350°C,
preferably
between 120 °C and 250 °C and more preferably between 130
°C and
200°C,
~ an outlet temperature of the drying gas of 40 °C to 120 °C,
~ a volumetric flow of the spray gas of 1 Nm3/h to 15 Nm3/h,
~ a volumetric flow of the drying gas of 15 Nm3lh to 1500 Nm3/h,
0 preferably 15 Nm3/h to 150 Nm3/h, and
d) separating the dried solid fraction from the drying gas current in
conventional
manner.
~5 A third object of the invention is the use of the active substance base
BIBN4096 in
the form of spherically nanostructured microparticles which may be obtained by
the
process described above, for preparing an inhalation powder.
A fourth object of the present invention is an inhalation powder,
characterised in that
2o the spherically nanostructured particles may be obtained by the process
according to
the invention described above.
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Experimental section
1 J Methods of measurement
a) Determining the particle size by laser diffraction (Fraunhofer
diffraction):
Method of
measurement: In order to determine the particle size, the powder is placed
in a laser diffraction spectrometer by means of a dispersing
o unit. By the median value X5o is meant the particle size
below which 50% of the particles are found. The Q~5.8~ value
describes the percentage proportion of the particles which
are less than 5.8 pm in size.
Measuring
~5 equipment: Laser diffraction spectrometer (HELOS), Messrs. Sympatec
Software: WINDOX 4 Version 3.3/REL 1 for Examples 1 to 3 and
Version 4 for Examples 4 to 6
Dispersing unit: RODOS / dispersing pressure: 3 bar
Focal length: 100 mm [measuring range: 0.9.....175pm]
2o Evaluation mode: HRLD (V 3.3 Rel. 1)
b) Determining the specific surface:
Method of
25 measurement: The specific surface is determined by exposing the powder
sample to a nitrogen atmosphere at different pressures.
Cooling the sample causes the nitrogen molecules to be
condensed on the surface of the particles. The quantity of
condensed nitrogen is determined by means of the
3o pressure drop in the system and the specific surface of the
sample is calculated by means of the surface nitrogen
requirement and the weight of the sample.
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Measuring
equipment Tri Star Multi Point BET, Messrs. Micromeritics
Heating station: VacPrep 061, Messrs. Micromeritics
Heating: about 12 h / 40 °C
Analytical parameters
Sample container: '/2 inch; with "filler rod"
Methods of analysis: 16 point BET surface measurement
0.05 to 0.20 p/p0
o absolute pressure tolerance: 5.0 mm Hg
relative pressure tolerance: 5.0%
speed of evacuation: 50.0 mm Hg/second
evacuation threshold: 10.0 mm Hg
duration: 0.1 h
~5 void volume: lowering of Dewar vessel,
t: 0.5 h
retention time: 20 seconds
Minimum equilibration time: 600 seconds
Adsorbent: nitrogen
2o c) Determining the droplet size by laser diffraction (according to Mie):
Measuring
equipment: Laser diffraction spectrometer (HELOS), Messrs. Sympatec
Software: WINDOX Version 4
2s Focal length: 100 mm [Measuring range: 0.9.....175 Nm]
Method of
measurement: The droplet size is determined by removing the nozzle
from the spray drier and placing the spray in the upper
third of the spray cone centrally in the laser beam. The
3o measurement is taken at ambient temperature with water
as the reference medium under otherwise identical
conditions.
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2) Examples of spray parameters
Example 1: Spray parameter, suitable for an alcoholic BIBN4096 solution
(modified BUCHI spray drier):
Concentration of solution/ 7 g BIBN 4096 in 100 ml
composition solvent ethanol/methanol/H20
molar ratio: 1 : 1 : 2.3
Droplet size Q~S,g~ 46% (evaluated according to
Mie);
(reference solution: Hz0 at 51 % (evaluated according to
ambient
temperature) Fraunhofer)
6.3 ~m (evaluated according
to Mie);
5.7 pm (evaluated according
to
Fraunhofer)
volumetric flow "spray rate" 18 ml / min
spray pressure (nozzle type) 2.9 bar overpressure (N2)
(BiJCHI spray nozzle 0.7 mm,
Art. no. 04364)
volumetric flow "atomising pressure"1775 standard litres / h
(nozzle type) (8(JCHI spray nozzle 0.7 mm,
Art. no. 04364)
entry temperature 150 C
exit temperature 100 C
volumetric flow "drying gas" 30 standard m3 / h
cross section of drying tower 105 mm
Characterisation of the solid particles obtained:
particle size Xso 1.9 pm
Q(5.8) ~ 98.3%
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Example 2: Spray parameter, suitable for an alcoholic BIBN4096 solution
(modified
BUCHI spray drier):
Concentration of solution/ 7 g BIBN 4096 in 100 m1
composition of solvent ethanol/methanol/H20
molar ratio: 1 : 1 : 2.3
Droplet size Q~5.s~ 27% (evaluated according to
Mie)
(reference solution: H20 at ambient39% (evaluated according to
temperature) Fraunhofer)
X5o 8.9 ~m (evaluated according
to Mie)
7.3 Nm (evaluated according
to
Fraunhofer)
volumetric flow "spray rate" 18 ml / min
spray pressure (nozzle type) 2.9 bar overpressure (N2)
(BUCHI spray nozzle 0.7 mm,
Art. no. 04364)
volumetric flow "atomising pressure"1482 standard litres / h
(nozzle type) (8tJCHl spray nozzle 0.7 mm,
Art. no. 04364)
entry temperature 150 C
exit temperature 100 C
volumetric flow of "drying gas" 30 standard m3 l h
cross section of drying tower 105 mm
Characterisation of the solid particles obtained:
particle size X5o ( 2.4 pm
Q(s.s> ~ 87°l0
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Examale 3: Spray parameter, suitable for an alcoholic BIBN4096 solution
(modified
BUCHI spray drier):
Concentration of solution/ 7.4 g BIBN 4096 in 100 g
composition of solvent ethanol/methanol/H20
molar ratio: 1 : 1 : 2.3
Droplet size Q~5.8~ < 10%
(reference solution: H20 at ambient
temperature)
X5
17 m
volumetric flow "spray rate" 1.04 I / h
spray pressure (nozzle type) 0.8 bar overpressure (N2) (8(JCHI
spray nozzle 0.7 mm, Art. no.
04364)
volumetric flow "atomising pressure"0.6 kg / h (8UCHI spray nozzle
0.7
(nozzle type) mm, Art. no. 04364)
entry temperature 150 C
exit temperature 100 C
volumetric flow "drying gas" 35-36 standard m3 / h
cross section of drying tower 105 mm
Characterisation of the solid particles obtained:
particle size Xso ~ 5.7 pm
Qc5.8~ ~ 50.7%
Specific surface Sm ~ 19.6 m2/g
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Example 4: Spray parameter, suitable for an alcoholic BIBN4096 solution
(modified
BUCHI spray drier):
Concentration of solution/ 7.0 g BIBN 4096 in 100 g
composition of solvent ethanol/methanol/H20
molar ratio: 1 : 1 : 2.3
Droplet size Q~S.s~ 59%
(reference solution: H20 at ambient
temperature)
X5
6.5 m
volumetric flow "spray rate" 1.08 I / h
spray pressure (nozzle type) 5.5 bar overpressure (N2) (BUCHI
spray nozzle 0. 7 mm, Art.
no. 04364)
volumetric flow "atomising pressure"3.4 kg / h (BIJCHI spray nozzle
0.7
(nozzle type) mm, Art. no. 04364)
entry temperature 150 C
exit temperature 95 C
volumetric flow "drying gas" 36 standard m3 / h
cross section of drying tower 105 mm
Characterisation of the solid particles obtained:
particle size Xso ~ 1.4 pm
Q~S.$> ~ 99.7%
Specific surface Sm 7.3 m2/g
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Example 5: Spray parameter, suitable for an alcoholic BIBN4096 solution
(modified
BUCHI spray drier):
Concentration of solution/ 9.9 g BIBN 4096 in 100 g ethanoI/H20
composition of solvent molar ratio: 2 : 3
Droplet size Q~5,8~ 59%
(reference solution: H20 at ambient
temperature)
X50
6.5 m
volumetric flow "spray rate" 1.2 I / h
spray pressure (nozzle type) 5.4 bar overpressure (N2)
(BUCHI spray nozzle 0.7 mm,
Art. no. 04364)
volumetric flow "atomising pressure"3.4 kg / h
(nozzle type) (BUCHI spray nozzle 0.7 mm,
Art. no. 04364)
entry temperature 150 C
exit temperature 101 C
volumetric flow "drying gas" 36 standard m3 / h
cross section of drying tower 105 mm
s Characterisation of the solid particles obtained:
particle size X5o 2.7 Nm
Q~S.e~ ~ 90.0%
Specific surface Sm 5.7 m2/g
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Example 6: Spray parameter, suitable for an alcoholic BIBN4096 solution
(modified
BUCHI spray drier):
Concentration of solution/ 4.0 g BIBN 4096 in 100 g ethanol/HZO
composition of solvent molar ratio: 2 : 3
Droplet size Q~5.8~ 59%
(reference solution: H20 at ambient
temperature)
X50
6.5 m
volumetric flow "spray rate" 1.2 I / h
spray pressure (nozzle type) 5.5 bar overpressure (N2)
(8UCHI spray nozzle 0.7 mm,
Art. no. 04364)
volumetric flow "atomising pressure"3.4 kg / h
(nozzle type)
(BUCHI spray nozzle 0.7 mm,
Art. no. 04364)
entry temperature 150 C
exit temperature 100 C
volumetric flow "drying gas" 36 standard m3 / h
cross section of drying tower 105 mm
Characterisation of the solid particles obtained:
particle size X5o 1.5 Nm
Q~5.8~ ~ 99.7%
Specific surface Sm 7.5 m2/g
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-19-
Brief description of the Figures
Figures 1 to 6 show photographs of microparticles of the active substance base
BIBN4096 prepared from an alcoholic spray solution by the method according to
the
invention.
CA 02476621 2004-08-17
