U.S. patent application number 11/416640 was filed with the patent office on 2006-12-14 for particle formation.
Invention is credited to Darren Gilbert, Andreas Kordikowski, Srinivas Palakodaty.
Application Number | 20060279011 11/416640 |
Document ID | / |
Family ID | 9918862 |
Filed Date | 2006-12-14 |
United States Patent
Application |
20060279011 |
Kind Code |
A1 |
Palakodaty; Srinivas ; et
al. |
December 14, 2006 |
Particle formation
Abstract
Method for preparing a target substance in particulate form,
comprising introducing into a particle formation vessel, through
separate first and second fluid inlets respectively, (a) a "target
solution/suspension" of the substance in a fluid vehicle and (b) a
compressed fluid anti-solvent, and allowing the anti-solvent to
extract the vehicle so as to form particles of the substance,
wherein the anti-solvent fluid has a sonic, near-sonic or
supersonic velocity as it enters the vessel, and wherein the
anti-solvent and the target solution/suspension enter the vessel at
different locations and meet downstream (in the direction of
anti-solvent flow) of the second fluid inlet. Also provided is
apparatus for use in such a method.
Inventors: |
Palakodaty; Srinivas;
(Foster City, CA) ; Kordikowski; Andreas; (Sent
Cugat del Valles, ES) ; Gilbert; Darren; (Bradford,
GB) |
Correspondence
Address: |
NEKTAR THERAPEUTICS
150 INDUSTRIAL ROAD
SAN CARLOS
CA
94070
US
|
Family ID: |
9918862 |
Appl. No.: |
11/416640 |
Filed: |
May 3, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10197689 |
Jul 17, 2002 |
7087197 |
|
|
11416640 |
May 3, 2006 |
|
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Current U.S.
Class: |
264/11 |
Current CPC
Class: |
B01J 2/04 20130101 |
Class at
Publication: |
264/011 |
International
Class: |
B29B 9/00 20060101
B29B009/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 20, 2001 |
GB |
0117696.5 |
Claims
1. A method for preparing a pharmaceutical substance in particulate
form, the method comprising: separately introducing into a particle
formation vessel the substance in a fluid vehicle through a first
fluid inlet; separately introducing into the particle formation
vessel a compressed fluid anti-solvent for the substance through a
second fluid inlet; and allowing the compressed fluid anti-solvent
to extract the fluid vehicle from the substance to form particles
of the substance, wherein the compressed fluid anti-solvent has a
sonic, near-sonic or supersonic velocity as it enters the particle
formation vessel, and wherein the compressed fluid anti-solvent and
the substance in the fluid vehicle enter the particle formation
vessel at different locations and contact each other after their
point of entry.
2. The method of claim 1, wherein the substance in the fluid
vehicle is a solution, a suspension or a combination thereof.
3. The method of claim 2, wherein the compressed fluid anti-solvent
is a supercritical or near-critical fluid.
4. The method of claim 3, wherein the supercritical fluid or
near-critical fluid contains a compound selected from the group
consisting of carbon dioxide, nitrogen, nitrous oxide, sulfur
hexafluoride, xenon, ethylene, chlorotrifluoromethane, ethane,
trifluoromethane, helium, neon, derivatives thereof and
combinations thereof.
5. The method of claim 1, wherein: the pressure in the particle
formation vessel is P.sub.1; and the compressed fluid anti-solvent
is introduced through a restricted inlet so as to have a back
pressure of P.sub.2 as it is introduced into the particle formation
vessel, where P.sub.2 is greater than P.sub.1.
6. The method of claim 5, wherein: the temperature in the particle
formation vessel is T.sub.1; and the compressed fluid anti-solvent
is introduced into the particle formation vessel at a temperature
T.sub.2, where T.sub.2 is greater than T.sub.1.
7. The method of claim 6, wherein T.sub.1 and T.sub.2 are such that
Joule-Thomson cooling of the compressed fluid anti-solvent as it
enters the particle formation vessel does not reduce the
temperature of the compressed fluid anti-solvent to below a
critical temperature T.sub.c of the anti-solvent.
8. The method of claim 7, wherein P.sub.1, P.sub.2, T.sub.1 and
T.sub.2 are such that the compressed fluid anti-solvent has a
sonic, near-sonic or supersonic velocity as it enters the particle
formation vessel.
9. The method of claim 8, wherein: the compressed fluid
anti-solvent is supercritical or near-critical carbon dioxide;
P.sub.1 is between about 75 bar and about 350 bar; P.sub.2 is
between about 250 bar and about 350 bar; T.sub.1 is between about
31.degree. C. and about 100.degree. C.; and T.sub.2 is between
about 80.degree. C. and about 170.degree. C.,
10. The method of claim 9, wherein the carbon dioxide has a flow
rate of between about 170 g/min and about 200 g/min; and P.sub.1
and P.sub.2 have a difference between about 170 bar and about 250
bar.
11. The method of claim 6, wherein: P.sub.1 is greater than a
critical pressure P.sub.c of the anti-solvent, T.sub.1 is greater
than a critical temperature T.sub.c of the anti-solvent; and
T.sub.1 and T.sub.2 are such that the temperature of the compressed
fluid anti-solvent does not fall below T.sub.c within the particle
formation vessel.
12. The method of claim 2, wherein on entering the particle
formation vessel, the compressed fluid anti-solvent has a Mach
number between about 0.8 and about 1.5.
13. The method of claim 2, wherein the near-sonic, sonic or
supersonic velocity of the compressed fluid anti-solvent is
achieved by introducing the compressed fluid anti-solvent into the
particle formation vessel as a single stream through a convergent
nozzle, without the aid of further mechanical, electrical and/or
magnetic input.
14. The method of claim 2, wherein a Mach disk is generated in the
compressed fluid anti-solvent as it enters the particle formation
vessel.
15. The method of claim 14, wherein shock waves from the Mach disk
propagate in the direction of the compressed fluid anti-solvent
flow.
16. The method of claim 2, wherein the compressed fluid
anti-solvent is a supercritical fluid.
17. The method of claim 2, wherein the fluid vehicle comprises two
or more fluids which are mixed in situ at or immediately before
their contact with the compressed fluid anti-solvent.
18. The method of claim 17, wherein the two or more fluids each
carry one or more substances that are to be combined in the
particle formation vessel.
19. The method of claim 2, wherein: the compressed fluid
anti-solvent, having a kinetic energy, disperses the substance in
the fluid vehicle by transferring the kinetic energy from the
compressed fluid anti-solvent to the fluid vehicle; and the kinetic
energy of the compressed fluid anti-solvent extracts the fluid
vehicle from the substance.
20. The method of claim 2, wherein the compressed fluid
anti-solvent and the substance in the fluid vehicle contact each
other immediately downstream of the point of compressed fluid
anti-solvent entry into the particle formation vessel.
21. The method of claim 20, wherein the contact between the
compressed fluid anti-solvent and the substance in the fluid
vehicle occurs between about 0.5 seconds and about 10 seconds of
the compressed fluid anti-solvent entering the particle formation
vessel.
22. The method of claim 21, wherein: the second fluid inlet has an
outlet opening; and the contact between the fluid anti-solvent and
the substance in the fluid vehicle occurs at a distance from the
compressed fluid anti-solvent entering the particle formation
vessel of between about 10 and about 40 times a diameter of the
outlet opening of the second fluid inlet.
23. The method of claim 21, wherein the contact between the fluid
anti-solvent and the substance in the fluid vehicle occurs at a
distance from the compressed fluid anti-solvent entering the
particle formation vessel of between about 2 mm and about 8 mm.
24. The method of claim 2, further comprising providing controlled
agitation within the particle formation vessel in the region of
fluid contact.
25. The method of claim 31, wherein the controlled agitation is
selected from a list comprising sonication and stirring.
26. The method of claim 25, wherein the stirring is selected from a
list of stirring methods comprising a turbine, a propeller, a
paddle, and an impeller.
27. The method of claim 2, wherein the substance in the fluid
vehicle is introduced directly into the flow of the compressed
fluid anti-solvent.
28. The method of claim 27, wherein the first fluid inlet
terminates inside the flow of the compressed fluid anti-solvent
coming out of the second fluid inlet.
29. The method of claim 2, wherein the substance in the fluid
vehicle and the compressed fluid anti-solvent meet, the angle
between their axes of flow is between about 70.degree. and about
110.degree..
30. The method of claim 2, wherein the fluid vehicle comprises a
fluid with a boiling point greater than about 150.degree. C.
31. The method of claim 30, wherein the pharmaceutical is
salmeterol xinafoate, risperodone-(9-hydroxy)-palmitate,
derivatives thereof, and combinations thereof.
32. The method of claim 6, wherein P.sub.1, P.sub.2, T.sub.1 and
T.sub.2 are selected so as to form particles of the substance
having a volume mean diameter of less than 5 .mu.m.
33. The method of claim 32, wherein P.sub.1, P.sub.2, T.sub.1 and
T.sub.2 are selected so as to form particles of the substance
having a volume mean diameter of less than 1 .mu.m.
34. The method of claim 6, wherein P.sub.1, P.sub.2, T.sub.1 and
T.sub.2 are selected so as to form particles of the substance
having a size distribution with a standard deviation of 2.5 or
less.
35. The method of claim 2, wherein the compressed fluid
anti-solvent contains one or more modifiers.
36. The method of claim 35, wherein the one or more modifiers are
selected from the group of water, methanol, ethanol, isopropanol,
and acetone.
37. The method of claim 35, wherein the one or more modifiers
constitutes between about 1 mole % and about 40 mole % of the
anti-solvent fluid.
38. A method for preparing a substance in particulate form, the
method comprising: introducing into a particle formation vessel the
substance in a fluid vehicle through a first fluid inlet, wherein
the particle formation vessel has a pressure P.sub.1 and a
Temperature T.sub.1; introducing into the particle formation vessel
a compressed fluid anti-solvent for the substance through a second
fluid inlet, wherein the compressed fluid anti-solvent is
introduced through a restricted inlet so as to have a back pressure
of P.sub.2 so that P.sub.2 is greater than P.sub.1, wherein the
compressed fluid anti-solvent has a temperature T.sub.2 so that
T.sub.2 is greater than T.sub.1, and wherein T.sub.1 and T.sub.2
are such that Joule-Thomson cooling of the compressed fluid
anti-solvent as it enters the particle formation vessel does not
reduce temperature of the compressed fluid anti-solvent to below
that required of it to produce particles; and allowing the
compressed fluid anti-solvent to extract the fluid vehicle from the
substance to form particles of the substance, wherein the
compressed fluid anti-solvent has a sonic, near-sonic or supersonic
velocity as it enters the particle formation vessel, wherein the
compressed fluid anti-solvent and the substance in the fluid
vehicle enter the particle formation vessel at different locations
and meet downstream in the particle formation vessel.
39. A method for preparing a pharmaceutically active substance in
particulate form, the method comprising: introducing into a
particle formation vessel the pharmaceutically active substance in
a fluid vehicle through a first fluid inlet; introducing into the
particle formation vessel near-critical or supercritical carbon
dioxide through a second fluid inlet; and allowing the
near-critical or supercritical carbon dioxide to extract the fluid
vehicle from the pharmaceutically active substance to form
particles of the pharmaceutically active substance, wherein the
near-critical or supercritical carbon dioxide has a sonic,
near-sonic or supersonic velocity as it enters the particle
formation vessel, wherein the near-critical or supercritical carbon
dioxide and the pharmaceutically active substance in the fluid
vehicle enter the particle formation vessel at different locations
and meet downstream in the particle formation vessel.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of co-pending U.S. patent
application Ser. No. 10/197,689, filed Jul. 17, 2002, which is
herein incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] This invention relates to methods and apparatus for forming
particles of a target substance.
BACKGROUND TO THE INVENTIOn
[0003] It is known to use a compressed fluid, typically a
supercritical or near-critical fluid, as an anti-solvent to
precipitate particles of a substance of interest (a "target
substance") from solution or suspension. The basic technique is
known as "GAS" (Gas Anti-Solvent) precipitation [Gallagher et al,
"Supercritical Fluid Science and Technology", ACS Symp. Ser., 406,
p334 (1989)]. Versions of it have been disclosed for instance in
EP-0 322 687 and WO-90/03782, which are hereby incorporated in
their entirety by reference.
[0004] In one particular version known as SEDS.TM. (Solution
Enhanced Dispersion by Supercritical fluids), a target substance is
dissolved or suspended in an appropriate fluid vehicle, and the
resulting "target solution/suspension" then co-introduced into a
particle formation vessel with an anti-solvent fluid (usually
supercritical) in which the vehicle is soluble. The co-introduction
is effected in a particular way, such that: [0005] the target
solution/suspension and the anti-solvent both meet and enter the
vessel at substantially the same point; and [0006] at that point,
the mechanical energy of the anti-solvent serves to disperse the
target solution/suspension (ie, to break it up into individual
fluid elements) at the same time as the anti-solvent extracts the
vehicle so as to cause particle formation.
[0007] Thus, in SEDS.TM., the compressed fluid serves not only as
an anti-solvent but also as a mechanical dispersing agent. The
simultaneity of fluid contact, dispersion and particle formation
provides a high degree of control over the physicochemical
properties of the particulate product.
[0008] Versions of SEDS.TM. are described in WO-95/01221,
WO-96/00610, WO-98/36825, WO-99/44733, WO-99/59710, WO-01/03821,
WO-01/15664 and WO-02/38127. Other SEDS.TM. processes are described
in WO-99/52507, WO-99/52550, WO-00/30612, WO-00/30613 and
WO-00/67892, all of which are hereby incorporated in their entirety
by reference
[0009] Another version of the GAS technique is described in
WO-97/31691, in which a special form of two-fluid nozzle is used to
introduce a "target solution/suspension" and an energising gas into
a particle formation vessel containing a supercritical
anti-solvent. The energising gas can be the same as the
anti-solvent fluid. Within the nozzle, a restriction generates
sonic waves in the energising gas/anti-solvent flow and focusses
them back (ie, in a direction opposite to that of the energising
gas flow) on the outlet of the target solution/suspension passage,
resulting in mixing of the fluids within the nozzle before they
enter the particle formation vessel. It is suggested that where the
energising gas is the same as the anti-solvent (typically
supercritical carbon dioxide), its flow rate could be sufficiently
high to obtain a sonic velocity at the nozzle outlet. However, the
authors do not appear ever to have achieved such high velocities in
their experimental examples.
[0010] Other modifications have been made to the basic GAS process
in order to affect atomisation of the target solution/suspension at
the point of its contact with the compressed fluid anti-solvent.
For example, U.S. Pat. No. 5,770,559 describes a GAS precipitation
process in which a target solution is introduced, using a sonicated
spray nozzle, into a pressure vessel containing a supercritical or
near-critical anti-solvent fluid--see also Randolph et al in
Biotechnol. Prog., 1993, 9, 429-435.
[0011] It would be generally desirable to provide alternative
particle formation techniques which combined one or more of the
advantages of the prior art methods with a broader applicability
(for instance, for a wider range of target substances, vehicles
and/or anti-solvents) and/or a higher degree of control over the
product characteristics. In particular it is generally desirable,
especially for pharmaceutical substances, to be able to produce
small (even sub-micron) particles with narrow size
distributions.
STATEMENTS OF THE INVENTION
[0012] According to a first aspect of the present invention there
is provided a method for preparing a target substance in
particulate form, the method comprising introducing into a particle
formation vessel, through separate first and second fluid inlet
means respectively, (a) a solution or suspension of the target
substance in a fluid vehicle (the "target solution/suspension") and
(b) a compressed fluid anti-solvent for the substance, and allowing
the anti-solvent fluid to extract the vehicle from the target
solution/suspension so as to form particles of the target
substance, wherein the anti-solvent fluid has a sonic, near-sonic
or supersonic velocity as it enters the particle formation vessel,
and wherein the anti-solvent and the target solution/suspension
enter the particle formation vessel at different locations and meet
downstream (in the direction of anti-solvent flow) of the second
fluid inlet means.
[0013] By "sonic velocity-" and "supersonic velocity" is meant
respectively that the velocity of the anti-solvent fluid as it
enters the vessel is the same as or greater than the velocity of
sound in that fluid at that point. By "near-sonic velocity" is
meant that the anti-solvent velocity on entry into the vessel is
slightly lower than, but close to, the velocity of sound in that
fluid at that point--for instance its "Mach number" M (the ratio of
its actual speed to the speed of sound) is greater than 0.8,
preferably greater than 0.9 or 0.95. Generally speaking, in the
method of the invention, the Mach number for the anti-solvent fluid
on entering the particle formation vessel may be between 0.8 and
1.5, preferably between 0.9 and 1.3.
[0014] A near-sonic, sonic or supersonic anti-solvent velocity may
be achieved by selecting appropriate operating conditions, in
particular the temperature and pressure of the fluid as it enters
the particle formation vessel, the temperature and pressure within
the vessel (which may be controlled in conventional manner, for
instance using an oven and a back pressure regulator) and the
geometry (in particular size) of the inlet through which the
anti-solvent is introduced into the vessel.
[0015] References in this specification to a fluid entering a
vessel are to the fluid exiting an inlet means (for example, a
nozzle) used to introduce the fluid into the vessel. For these
purposes, therefore, the inlet means is to be considered as
upstream of the vessel in the direction of fluid flow, although
parts of it (in particular its outlet) may be located physically
within the vessel.
[0016] There needs to be a drop in pressure as the anti-solvent
fluid enters the particle formation vessel. This is typically
achieved by imparting a relatively high "back pressure" to the
anti-solvent (by using a high anti-solvent flow rate and forcing it
through a restriction such as a nozzle) and maintaining the vessel
at a significantly lower pressure.
[0017] However, this pressure reduction can cause undesirable
Joule-Thomson cooling of the anti-solvent. Accordingly, the
temperature of the anti-solvent upstream of the particle formation
vessel needs to be sufficiently high that the fluid remains at an
appropriate temperature (typically above its critical temperature
T.sub.c), even after expanding into the particle formation vessel.
The method of the invention thus preferably includes pre-heating
the anti-solvent fluid, upstream of the particle formation vessel,
to a temperature such as to compensate for its Joule-Thomson
cooling as it enters the vessel.
[0018] Thus, the first aspect of the present invention may be seen
as a method for preparing a target substance in particulate form,
the method comprising introducing into a particle formation vessel
(a) a solution or suspension of the target substance in a fluid
vehicle (the "target solution/suspension") and (b) a compressed
fluid anti-solvent for the substance, and allowing the anti-solvent
fluid to extract the vehicle from the target solution/suspension so
as to form particles of the target substance, wherein (i) the
pressure in the particle formation vessel is P.sub.1 which is
preferably greater than the critical pressure P.sub.c of the
anti-solvent, (ii) the anti-solvent is introduced through a
restricted inlet so as to have a back pressure of P.sub.2, where
P.sub.2 is greater than P.sub.1, (iii) the temperature in the
particle formation vessel is T.sub.1 which is preferably greater
than the critical temperature T.sub.c of the anti-solvent, (iv) the
anti-solvent is introduced into the vessel at a temperature
T.sub.2, where T.sub.2 is greater than T.sub.1, (v) T.sub.1 and
T.sub.2 are such that Joule-Thomson cooling of the anti-solvent as
it enters the vessel does not reduce the anti-solvent temperature
to below that required of it at the point of particle formation
(and are preferably such that the anti-solvent temperature does not
fall below T.sub.c within the vessel) and (vi) P.sub.1, P.sub.2,
T.sub.1 and T.sub.2 are such that the anti-solvent fluid has a
sonic, near-sonic or supersonic velocity as it enters the particle
formation vessel.
[0019] Again the anti-solvent and the target solution/suspension
must be introduced separately into the particle formation vessel
and contact each other downstream of (preferably immediately
downstream of) the point of anti-solvent entry into the vessel.
[0020] The anti-solvent expansion as it enters the particle
formation vessel is isenthalpic. Thus, an appropriate temperature
for the anti-solvent upstream of the vessel may be derived from
enthalpy charts for the fluid, for instance as illustrated for
carbon dioxide in FIG. 1. (For CO.sub.2, the critical temperature
T.sub.c is 31.degree. C. (304 K) and the critical pressure P.sub.c
is 74 bar.) FIG. 1 shows how, when working with a pressure
reduction from 300 to 80 bar for the CO.sub.2 on entering the
particle formation vessel, the upstream temperature should be at
least 360 K (87.degree. C.) to achieve an appropriate temperature
of 308 K (35.degree. C.) or greater when the CO.sub.2 enters the
vessel.
[0021] Thus, a carbon dioxide anti-solvent is preferably introduced
with an upstream temperature of 80.degree. C. (353 K) or higher,
more preferably between 80.degree. C. and 170.degree. C. (443
K).
[0022] The pressures and temperatures needed to ensure a
near-sonic, sonic or supersonic velocity depend on the nature of
the anti-solvent fluid. In the case of a carbon dioxide
anti-solvent, for instance, in order to achieve a sonic or
supersonic velocity the operating conditions must satisfy the
formula: p o p i .ltoreq. [ 2 k + 1 ] k k - 1 ##EQU1## where
p.sub.i is the CO.sub.2 pressure upstream of entry into the
particle formation vessel and p.sub.o is the CO.sub.2 pressure
immediately on entry into the vessel, and k is the ratio of the
specific heats of CO.sub.2 at constant pressure (C.sub.p) and
constant volume (C.sub.v).
[0023] So, for example the CO.sub.2 may be introduced at a
temperature of 360 K (87.degree. C.) with an inlet pressure p.sub.i
of 300 bar, and the vessel may be at 310 K (37.degree. C.) and 80
bar (ie, the outlet pressure p.sub.o is 80 bar). At 310 K and 80
bar, k for CO.sub.2 is 8.78.sup.1. At 360 K and 300 bar, k is
2.29.sup.1. Taking a geometric average for k of 4.48, as the
CO.sub.2 exits the nozzle, then substituting these values into the
above equation gives p o p i = 0.267 ##EQU2## and .times. [ 2 k + 1
] k k - 1 = 0.274 ##EQU2.2## which confirms that the CO.sub.2 flow
is supersonic irrespective of the CO.sub.2 flow rate into the
vessel, so long as there is an appropriate pressure differential
between p.sub.i and p.sub.o. A suitable CO.sub.2 flow might be for
instance between 170 and 200 g/min. A suitable pressure drop as the
CO.sub.2 enters the particle formation vessel might be between 170
and 250 bar. .sup.1International thermodynamic tables of the fluid
state -3. Carbon dioxide, Angus et al, Pergamon Press, 1976
[0024] An alternative method for calculating the anti-solvent
velocity (again for carbon dioxide, using the same operating
conditions as above but with a vessel temperature of 40.degree. C.,
and introducing the CO.sub.2 through a nozzle of outlet diameter
0.2 mm) is:
(i) density of CO.sub.2 at 310 K and 80 bar.sup.1 is 0.33088
g/cm.sup.3,
(ii) therefore, volumetric flow of CO.sub.2 at 200 g/min (Q) is
200/0.33088=604.45 cm.sup.3/min.
(iii) Surface area (A) of the nozzle=3.14.times.10.sup.-4
cm.sup.2,
(iv) therefore velocity of CO.sub.2=Q/(A.times.60.times.100)=320.7
m/s.
(v) Speed of sound in CO.sub.2 at 310 K and 80 bar.sup.1 is 196.8
m/s.
(vi) Thus, the CO.sub.2 velocity is confirmed as being supersonic
under such conditions.
[0025] Although we do not wish to be bound by this theory, it is
believed that in the method of the invention, a so-called "Mach
disk" is generated in the anti-solvent flow downstream of the
second fluid inlet means. In this region the fluid velocity will
change abruptly to sub-sonic thus generating shock waves in the
fluids present (in effect a continuous, low volume, supersonic
boom). These shock waves are thought to aid mixing and dispersion
of the target solution/suspension with the anti-solvent. It is
unlikely that the waves will be ultrasonic as in for example the
system described in WO-97/31691. Moreover they will propagate in
the direction of the anti-solvent flow, rather than in a
counter-current sense as in for instance the nozzle described in
WO-97/31691 which reflects a sonic wave back towards a source of
energising gas.
[0026] The arrangement of the first and second inlet means will
preferably be such that the Mach disk is generated upstream (in the
direction of anti-solvent flow) of the point of entry of the target
solution/suspension into the particle formation vessel. It should
occur in line with the longitudinal axis of the second inlet means,
ie, in line with the direction of anti-solvent flow.
[0027] The near-sonic, sonic or supersonic anti-solvent velocity is
ideally achieved, in the method of the present invention, simply by
the use of appropriate anti-solvent flow rates, back pressures
and/or operating temperatures, and without the aid of mechanical,
electrical and/or magnetic input such as for example from
impellers, impinging surfaces especially within the anti-solvent
introducing means, electrical transducers and the like. Introducing
the anti-solvent via a convergent nozzle, ideally as a single fluid
stream, may also help in the achievement of appropriate fluid
velocities. Further "energising" fluid streams, such as those
required in the method of WO-97/31691, are not then needed in order
to achieve the desired level of control over the contact between
the target solution/suspension and the anti-solvent fluid.
[0028] The use of near-sonic, sonic or supersonic anti-solvent
velocities can allow achievement of smaller particle sizes and
narrower size distributions in GAS-based particle formation
processes. In particular it can allow the formation of small micro-
or even nano-particles, for instance of volume mean diameter less
than 5 .mu.m, preferably less than 2 .mu.m, more preferably less
than 1 .mu.m. Such particulate products preferably have narrow size
distributions, such as with a standard deviation of 2.5 or less,
more preferably 2.0 or less, most preferably 1.9 or even 1.8 or
less.
[0029] The use of near-sonic, sonic or supersonic anti-solvent
velocities also appears to lead to more efficient vehicle
extraction, thus potentially yielding particles with lower residual
solvent levels, less agglomeration and generally improved handling
properties.
[0030] The anti-solvent fluid must be in a compressed state, by
which is meant that it is above its vapour pressure, preferably
above atmospheric pressure, more preferably from 70 to 200 bar or
from 80 to 150 bar. More preferably "compressed" means above the
critical pressure P.sub.c for the fluid or fluid mixture concerned.
In practice, the pressure of the anti-solvent fluid is likely to be
in the range (1.01-9.0)P.sub.c, preferably (1.01-7.0)P.sub.c.
[0031] Thus, the anti-solvent is preferably a supercritical or
near-critical fluid, although it may alternatively be a compressed
liquid such as for instance liquid CO.sub.2.
[0032] As used herein, the term "supercritical fluid" means a fluid
at or above its critical pressure (P.sub.c) and critical
temperature (T.sub.c) simultaneously. In practice, the pressure of
the fluid is likely to be in the range (1.01-9.0)P.sub.c,
preferably (1.01-7.0)P.sub.c, and its temperature in the range
(1.01-4.0)T.sub.c (measured in Kelvin). However, some fluids (eg,
helium and neon) have particularly low critical pressures and
temperatures, and may need to be used under operating conditions
well in excess of (such as up to 200 times) those critical
values.
[0033] "Near-critical fluid" is here used to refer to a fluid which
is either (a) above its T.sub.c but slightly below its P.sub.c, (b)
above its P.sub.c but slightly below its T.sub.c or (c) slightly
below both its T.sub.c and its P.sub.c. The term "near-critical
fluid" thus encompasses both high pressure liquids, which are
fluids at or above their critical pressure but below (although
preferably close to) their critical temperature, and dense vapours,
which are fluids at or above their critical temperature but below
(although preferably close to) their critical pressure.
[0034] By way of example, a high pressure liquid might have a
pressure between about 1.01 and 9 times its P.sub.c, and a
temperature between about 0.5 and 0.99 times its T.sub.c. A dense
vapour might, correspondingly, have a pressure between about 0.5
and 0.99 times its P.sub.c, and a temperature between about 1.01
and 4 times its T.sub.c.
[0035] The terms "supercritical fluid" and "near-critical fluid"
each encompass a mixture of fluid types, so long as the mixture is
in the supercritical or near-critical state respectively.
[0036] In the method of the present invention, it may be preferred
that the operating temperature (ie, the temperature in the particle
formation vessel) be close to the critical temperature T.sub.c of
the mixture of anti-solvent and target solution/suspension formed
at the point of fluid contact. For example, the temperature might
be between 0.9 and 1.1 times T.sub.c (in Kelvin), preferably
between 0.95 and 1.05 times T.sub.c, more preferably between 0.97
and 1.03 or between 0.98 and 1.02 times T.sub.c, or perhaps between
1 and 1.05 or 1 and 1.03 or 1 and 1.02 times T.sub.c. This is
because at T.sub.c the velocity of sound in a fluid is
theoretically zero; near-sonic, sonic and supersonic velocities can
thus more readily be achieved, using lower anti-solvent flow rates,
as T.sub.c is approached.
[0037] The anti-solvent should be a compressed (preferably
supercritical or near-critical, more preferably supercritical)
fluid at its point of entry into the particle formation vessel and
preferably also within the vessel and throughout the particle
formation process. Thus, for a carbon dioxide anti-solvent the
temperature in the particle formation vessel is ideally greater
than 31.degree. C., for example between 31 and 100.degree. C.,
preferably between 31 and 70.degree. C., and the pressure greater
than 74 bar, for example between 75 and 350 bar.
[0038] Carbon dioxide is a highly suitable anti-solvent, but others
include nitrogen, nitrous oxide, sulphur hexafluoride, xenon,
ethylene, chlorotrifluoromethane, ethane, trifluoromethane and
noble gases such as helium or neon.
[0039] The anti-solvent must be miscible or substantially miscible
with the fluid vehicle at the point of their contact, so that the
anti-solvent can extract the vehicle from the target
solution/suspension. By "miscible" is meant that the two fluids are
miscible in all proportions, and "substantially miscible"
encompasses the situation where the fluids can mix sufficiently
well, under the operating conditions used, as to achieve the same
or a similar effect, ie, dissolution of the fluids in one another
and precipitation of the target substance. However the anti-solvent
must not, at the point of particle formation, extract or dissolve
the target substance. In other words, it must be chosen so that the
target substance is for all practical purposes (in particular,
under the chosen operating conditions and taking into account any
fluid modifiers present) insoluble or substantially insoluble in
it. Preferably the target substance is less than 10-3 mole %, more
preferably less than 10-5 mole %, soluble in the anti-solvent
fluid.
[0040] The anti-solvent fluid may optionally contain one or more
modifiers, for example water, methanol, ethanol, isopropanol or
acetone. A modifier (or co-solvent) may be described as a chemical
which, when added to a fluid such as a supercritical or
near-critical fluid, changes the intrinsic properties of that fluid
in or around its critical point, in particular its ability to
dissolve other materials. When used, a modifier preferably
constitutes not more than 40 mole %, more preferably not more than
20 mole %, and most preferably between 1 and 10 mole %, of the
anti-solvent fluid.
[0041] The vehicle is a fluid which is able to carry the target
substance in solution or suspension. It may be composed of one or
more component fluids, eg, it may be a mixture of two or more
solvents. It must be soluble (or substantially soluble) in the
chosen anti-solvent fluid at their point of contact. It may
contain, in solution or suspension, other materials apart from the
target substance.
[0042] The target solution/suspension may in particular comprise
two or more fluids which are mixed in situ at or immediately before
their contact with the anti-solvent. Such systems are described,
eg, in WO-96/00610 and WO-01/03821. The two or more fluids may
carry two or more target substances, to be combined in some way
(for instance, co-precipitated as a matrix, or one precipitated as
a coating around the other, or precipitated as the product of an in
situ reaction between the substances) at the point of particle
formation. Target substance(s) may also be carried in the
anti-solvent fluid as well as in the target
solution(s)/suspension(s).
[0043] The target substance may be any substance which needs to be
produced in particulate form. Examples include pharmaceuticals;
pharmaceutical excipients such as carriers; dyestuffs; cosmetics;
foodstuffs; coatings; agrochemicals; products of use in the
ceramics, explosives or photographic industries; etc . . . It may
be organic or inorganic, monomeric or polymeric. It is preferably
soluble or substantially soluble in the fluid vehicle, preferably
having a solubility in it of 10-4 mole % or greater under the
conditions under which the target solution is prepared (ie,
upstream of the point of particle formation).
[0044] In a preferred embodiment of the invention, the target
substance is for use in or as a pharmaceutical or pharmaceutical
excipient.
[0045] The target substance may be in a single or multi-component
form (eg, it could comprise an intimate mixture of two materials,
or one material in a matrix of another, or one material coated onto
a substrate of another, or other similar mixtures). The particulate
product, formed from the target substance using the method of the
invention, may also be in such a multi-component form--examples
include two pharmaceuticals intended for co-administration, or a
pharmaceutical together with a polymer carrier matrix. Such
products may be made (as described above) from
solutions/suspensions containing only single component starting
materials, provided the solutions/suspensions are contacted with
the anti-solvent fluid in the correct manner. The particulate
product may comprise a substance formed from an in situ reaction
(ie, immediately prior to, or on, contact with the anti-solvent)
between two or more reactant substances each carried by an
appropriate vehicle.
[0046] In the method of the invention, the anti-solvent and the
target solution/suspension are introduced separately into the
particle formation vessel (which is preferably the vessel in which
the formed particles are collected) and contact each other after
(preferably immediately after) their point of entry into the
vessel. In this way, particle formation can be made to occur at a
point where there is a high degree of control over conditions such
as the temperatures, pressures and flow rates of the fluids.
[0047] The fluids are ideally introduced in such a way that the
mechanical (kinetic) energy of the anti-solvent fluid can act to
disperse the target solution/suspension at the same time as it
extracts the vehicle; this again allows a high degree of control
over the physicochemical characteristics of the particulate
product, in particular the size and size distribution of the
particles and their solid state properties. "Disperse" in this
context refers generally to the transfer of kinetic energy from one
fluid to another, usually implying the formation of droplets, or of
other analogous fluid elements, of the fluid to which the kinetic
energy is transferred. Thus, the fluid inlet means used to
introduce the fluids should allow the mechanical energy (typically
the shearing action) of the anti-solvent flow to facilitate
intimate mixing of the fluids and to disperse them, at the point
where the fluids meet.
[0048] Introducing the two fluids separately in this way can help
prevent apparatus blockages at the point of anti-solvent entry, due
for example to the highly efficient extraction of the vehicle into
the anti-solvent under the operating conditions used.
[0049] Thus, the present invention may be seen as a modification of
the SEDS.TM. process, in which the target solution/suspension and
the anti-solvent fluid contact one another externally of their
respective (preferably separate) fluid inlets into the particle
formation vessel. A high degree of control is retained over the
mechanism for fluid contact, as in the basic SEDS.TM. process, and
this control may be achieved for example at least partly by
introducing the anti-solvent fluid with a sonic, near-sonic or
supersonic velocity. Other ways in which such control may be
achieved or improved upon include providing controlled agitation
within the particle formation vessel, in particular in the region
of fluid contact immediately downstream of the respective target
solution/suspension and anti-solvent inlets. For example, the
target solution/suspension may be dispersed onto a sonicating
surface at or immediately prior to its contact with the
anti-solvent fluid. Agitation may alternatively be achieved for
instance by stirring, such as with a turbine, propeller, paddle,
impeller or the like.
[0050] That said, the present invention may if necessary be
practised in the absence of such additional agitation means within
the particle formation vessel.
[0051] The target solution/suspension may be introduced into the
vessel through any suitable fluid inlet means, including one which
effects, or assists in effecting, controlled atomisation of the
solution/suspension.
[0052] Preferably the two fluids meet immediately downstream of the
point of anti-solvent entry. "Immediately" in this context implies
a sufficiently small time interval (between the anti-solvent
entering the particle formation vessel and its contact with the
target solution/suspension) as preferably still to allow transfer
of mechanical energy from the anti-solvent to the
solution/suspension so as to achieve dispersion. Nevertheless,
there is still preferably a short interval of time between
anti-solvent entry and fluid contact so as to eliminate, or
substantially eliminate or at least reduce, the risk of apparatus
blockage due to particle formation at the point of anti-solvent
entry. The timing of the fluid contact will depend on the natures
of the fluids, the target substance and the desired end product, as
well as on the size and geometry of the particle formation vessel
and the apparatus used to introduce the fluids and on the fluid
flow rates. The contact may occur within 0.5 to 10 seconds, more
preferably within 1 to 7 seconds, most preferably within 1.2 to 6
seconds, such as within 1.4 to 5.5 seconds, of the anti-solvent
entering the particle formation vessel.
[0053] The target solution/suspension is preferably introduced
directly into the anti-solvent flow. It preferably meets with the
anti-solvent flow at the point where the target solution/suspension
enters the vessel.
[0054] Preferably the outlet of the first fluid inlet means is
located vertically below that of the second fluid inlet means, and
the anti-solvent fluid flows into the particle formation vessel in
a vertically downwards direction.
[0055] At the point where the target solution/suspension and the
anti-solvent meet, the angle between their axes of flow may be from
0.degree. (ie, the two fluids are flowing in parallel directions)
to 180.degree. (ie, oppositely-directed flows). However, they
preferably meet at a point where they are flowing in approximately
perpendicular directions, ie, the angle between their axes of flow
is from 70 to 110.degree., more preferably from 80 to 100.degree.,
such as 90.degree..
[0056] Suitable fluid inlet means, which may be used to achieve the
form of fluid contact required by the first aspect of the
invention, is described below in connection with the second
aspect.
[0057] Use of such a fluid inlet system can allow SEDS.TM. and
other GAS-based particle formation techniques to be practised in
cases where the vehicle for the target solution/suspension is a
relatively high boiling fluid (eg, boiling point greater than about
150.degree. C., or even greater than 180.degree. C.) such as
dimethyl formamide (DMF), dimethyl sulphoxide (DMSO), dimethyl
acetamide (DMA), diethyl acetamide (DEA) or N-methyl pyrollidinone
(NMP), or where the target substance is temperature sensitive.
Since the anti-solvent and the target solution/suspension enter the
vessel separately, the latter can be maintained at a desired lower
temperature despite the use of a relatively high temperature for
the incoming anti-solvent. Moreover, the use of a sonic, near-sonic
or supersonic anti-solvent velocity can be sufficient to disperse
the target solution/suspension at relatively low operating
temperatures (ie, vessel temperatures)--again this assists in the
processing of temperature sensitive target substances and
vehicles.
[0058] When carrying out the present invention, the particle
formation vessel temperature and pressure are ideally controlled so
as to allow particle formation to occur at or substantially at the
point where the target solution/suspension meets the anti-solvent
fluid. The conditions in the vessel must generally be such that the
anti-solvent fluid, and the solution which is formed when it
extracts the vehicle, both remain in the compressed (preferably
supercritical or near-critical, more preferably supercritical) form
whilst in the vessel. For the supercritical, near-critical or
compressed solution, this means that at least one of its
constituent fluids (usually the anti-solvent fluid, which in
general will be the major constituent of the mixture) should be in
a compressed state at the time of particle formation. There should
at that time be a single-phase mixture of the vehicle and the
anti-solvent fluid, otherwise the particulate product might be
distributed between two or more fluid phases, in some of which it
might be able to redissolve. This is why the anti-solvent fluid
needs to be miscible or substantially miscible with the
vehicle.
[0059] The terms "supercritical solution", "near-critical solution"
and "compressed solution" mean respectively a supercritical,
near-critical or compressed fluid together with a fluid vehicle
which it has extracted and dissolved. The solution should itself
still be in the supercritical, near-critical or compressed state,
as the case may be, and exist as a single phase, at least within
the particle formation vessel.
[0060] Selection of appropriate operating conditions will be
influenced by the natures of the fluids involved (in particular,
their P.sub.c and T.sub.c values and their solubility and
miscibility characteristics) and also by the characteristics
desired of the particulate end product, for instance yield,
particle size and size distribution, purity, morphology, or
crystalline, polymorphic or isomeric form. Variables include the
flow rates of the anti-solvent fluid and the target
solution/suspension, the concentration of the target substance in
the vehicle, the temperature and pressure inside the particle
formation vessel, the anti-solvent temperature upstream of the
vessel and the geometry of the fluid inlets into the vessel, in
particular the size of the anti-solvent inlet. The method of the
invention preferably involves controlling one or more of these
variables so as to influence the physicochemical characteristics of
the particles formed.
[0061] The flow rate of the anti-solvent fluid relative to that of
the target solution/suspension, and its pressure and temperature,
should be sufficient to allow it to accommodate the vehicle, so
that it can extract the vehicle and hence cause particle formation.
The anti-solvent flow rate will generally be higher than that of
the target solution/suspension--typically, the ratio of the target
solution/suspension flow rate to the anti-solvent flow rate (both
measured at or immediately prior to the two fluids coming into
contact with one another) will be 0.001 or greater, preferably from
0.01 to 0.2, more preferably from about 0.03 to 0.1.
[0062] The anti-solvent flow rate will also generally be chosen to
ensure an excess of the anti-solvent over the vehicle when the
fluids come into contact, to minimise the risk of the vehicle
re-dissolving and/or agglomerating the particles formed. At the
point of extraction of the vehicle it may constitute from 1 to 80
mole %, preferably 50 mole % or less or 30 mole % or less, more
preferably from 1 to 20 mole % and most preferably from 1 to 5 mole
%, of the compressed fluid mixture formed.
[0063] Both the anti-solvent and the target solution/suspension are
ideally introduced into the particle formation vessel with a
smooth, continuous and preferably pulse-less or substantially
pulse-less flow. Conventional apparatus may be used to ensure such
fluid flows.
[0064] The method of the invention preferably additionally involves
collecting the particles following their formation, more preferably
in the particle formation vessel itself.
[0065] According to a second aspect of the present invention, there
is provided apparatus for use in preparing a target substance in
particulate form, and in particular for use in a method according
to the first aspect of the invention, the apparatus comprising:
(i) a particle formation vessel;
(ii) first fluid inlet means for introducing into the vessel a
solution or suspension of the target substance in a fluid vehicle
(the "target solution/suspension"); and
(iii) second fluid inlet means, separate from the first, for
introducing a compressed fluid anti-solvent into the particle
formation vessel;
[0066] wherein the first and second fluid inlet means are so
arranged that, in use, a target solution/suspension introduced
through the first and an anti-solvent introduced through the second
enter the particle formation vessel at different locations and meet
immediately downstream (in the direction of anti-solvent flow) of
the second fluid inlet means.
[0067] The first fluid inlet means suitably comprises a fluid inlet
tube, for instance of stainless steel, which might typically have
an internal diameter of from 0.1 to 0.2 mm, more preferably from
0.1 to 0.15 mm, and may have a tapered outlet section.
[0068] The second fluid inlet means preferably provides a
restriction at the point of fluid entry into the particle formation
vessel: for instance, the second fluid inlet means may comprise a
nozzle. Again it may suitably be made from stainless steel. It
preferably has at least one passage of internal diameter from for
instance 1 to 2 mm, more preferably from 1.3 to 1.9 mm, such as 1.6
mm. Again, it may have a tapered outlet section (ie, be a
"convergent"-type nozzle), with an angle of taper (with respect to
the longitudinal axis of the nozzle) typically in the range
10.degree. to 60.degree., preferably from 10.degree. to 50.degree.,
more preferably from 20.degree. to 40.degree., and most preferably
about 30.degree..
[0069] The opening at the outlet end (tip) of the nozzle will
preferably have a diameter in the range of 0.005 to 5 mm, more
preferably 0.05 to 2 mm, most preferably from 0.1 to 0.5 mm, for
instance about 0.1, 0.2, 0.3 or 0.35 mm.
[0070] The dimensions of the fluid inlet will naturally depend on
the scale on which the process is to be practised; for commercial
scale manufacture, for example, the above nozzle dimensions may be
up to ten times larger.
[0071] A nozzle of the above type may comprise more than one fluid
passage; for instance it may comprise two or more coaxial passages
such as in the nozzles described in WO-95/01221, WO-96/00610 and
WO-98/36825, particularly if additional fluids are to be introduced
into the system. One or more of the passages may be used to
introduce two or more fluids at the same time, and the inlets to
such passages may be modified accordingly.
[0072] The outlet of the first fluid inlet means (into the particle
formation vessel) is preferably immediately downstream, in the
direction of anti-solvent flow in use, of that of the second fluid
inlet means. A suitable separation for the two outlets is a short
distance such as from 0 to 50, preferably from 10 to 40, for
instance about 20 times the diameter of the outlet of the second
fluid inlet means. Suitable distances might lie from 0 to 10 mm or
from 0.1 to 10 mm, preferably from 2 to 8 mm, for instance about 4
mm. Again, they may depend on the scale of the process which the
inlet means are to be used for.
[0073] The outlet of the first fluid inlet means preferably has a
smaller cross sectional area than that of the second fluid inlet
means, more preferably less than 80% as large and most preferably
less than 70% or 65% as large. Preferably this outlet is positioned
such that, in use, it is within the flow of anti-solvent fluid
exiting the second fluid inlet means. Most preferred is an
arrangement in which the centre of the outlet of the first fluid
inlet means corresponds to the centre of the outlet of the second
fluid inlet means, ie, the centres of the two outlets are both
positioned on the central longitudinal axis of the second fluid
inlet means.
[0074] The first and second fluid inlet means are preferably
arranged so that at the point where the target solution/suspension
and the anti-solvent meet, the angle between their axes of flow is
from 70.degree. to 110.degree., more preferably from 80 to
100.degree., most preferably about 90.degree..
[0075] The first and second fluid inlet means may for convenience
be provided as part of a single fluid inlet assembly which may be
placed in fluid communication with the particle formation vessel
and with sources of the anti-solvent fluid and the target
solution/suspension.
[0076] Thus, according to a third aspect, the present invention
provides a fluid inlet assembly for use as part of apparatus
according to the second aspect of the invention, and/or in a method
according to the first aspect.
[0077] In apparatus according to the second aspect of the
invention, the particle formation vessel preferably contains
particle collection means, such as a filter, by which particles of
the target substance may be collected in the vessel in which they
form, downstream of the point of contact between the target
solution/suspension and the anti-solvent fluid.
[0078] The apparatus may additionally comprise a source of a
compressed (preferably supercritical or near-critical) fluid and/or
a source of a target solution or suspension. The former may itself
comprise means for altering the temperature and/or pressure of a
fluid so as to bring it into a compressed (preferably supercritical
or near-critical) state. The apparatus conveniently includes means
for controlling the pressure in the particle formation vessel, for
example a back pressure regulator downstream of the vessel, and/or
means (such as an oven) for controlling the temperature in the
vessel. The vessel is conveniently a pressure vessel and should be
capable of withstanding the pressures necessary to maintain
compressed (preferably supercritical or near-critical) conditions
during the particle formation process, as described above in
connection with the method of the invention.
[0079] Because embodiments of the present invention are modified
versions of the inventions disclosed in WO-95/01221, WO-96/00610,
WO-98/36825, WO-99/44733, WO-99/59710, WO-01/03821, WO-01/15664 and
WO-02/38127, technical features described in those documents, for
instance regarding the selection of appropriate reagents and
operating conditions, can apply also to the present invention. The
eight earlier documents are therefore intended to be read together
with the present application.
[0080] In this specification the term "substantially", when applied
to a condition, is meant to encompass the exact condition (eg,
exact simultaneity) as well as conditions which are (for practical
purposes, taking into account the degree of precision with which
such conditions can be measured and achieved) close to that exact
condition, and/or which are similar enough to that exact condition
as to achieve, in context, the same or a very similar effect.
[0081] References to solubilities and miscibilities, unless
otherwise stated, are to the relevant fluid characteristics under
the operating conditions used, ie, under the chosen conditions of
temperature and pressure and taking into account any modifiers
present in the fluids.
[0082] The present invention will now be illustrated with reference
to the following non-limiting examples and the accompanying
figures, of which:
[0083] FIG. 1 is a plot of the enthalpy variation of CO.sub.2 with
temperature and pressure, illustrating the change in CO.sub.2
temperature during its isenthalpic expansion;
[0084] FIG. 2 illustrates schematically apparatus suitable for use
in carrying out a method according to the present invention;
[0085] FIGS. 3 to 5 are schematic longitudinal cross sections and
an under plan view respectively of parts of a fluid inlet assembly
useable with the FIG. 2 apparatus;
[0086] FIGS. 6 to 9 are SEM (scanning electron microscope)
photographs of the products of Examples A1, A2, A5 and A6 (below)
respectively;
[0087] FIGS. 10 and 10B show particle size distributions for the
product of Example B1;
[0088] FIGS. 11A and 11B show particle size distributions for the
product of Example B2;
[0089] FIGS. 12A and 12B show particle size distributions for the
product of Example B3;
[0090] FIGS. 13 and 14 are SEM photographs of the products of
Examples D1 and D2 respectively;
[0091] FIGS. 15A and 15B show particle size distributions for the
product of Example D1;
[0092] FIGS. 16A and 16B show particle size distributions for the
product of Example D2; and
[0093] FIGS. 17 and 18 are SEM photographs of the products of
Examples E2 and E3 respectively.
DETAILED DESCRIPTION
[0094] FIG. 2 shows apparatus suitable for carrying out methods in
accordance with the present invention. Item 1 is a particle
formation vessel, within which the temperature and pressure can be
controlled by means of the heating jacket 2 and back pressure
regulator 3. The vessel 1 contains a particle collection device
(not shown) such as a filter, filter basket or filter bag. A fluid
inlet assembly 4 allows introduction of a compressed (typically
supercritical or near-critical) fluid anti-solvent from source 5
and one or more target solutions/suspensions from sources such as 6
and 7. The items labelled 8 are pumps, and 9 is a cooler. A
recycling system 11 allows solvent recovery.
[0095] The fluid inlet assembly 4 may for example take the form
shown in FIGS. 3 to 5. FIG. 3 shows the assembly schematically, in
use with the particle formation vessel 1 of the FIG. 2 apparatus.
Nozzle 21 is for introduction of the anti-solvent fluid. It has
only a single passage of circular cross section, with a circular
outlet 22. Alternatively, a multi-component nozzle may be used,
with anti-solvent introduced through one or more of its passages
and the remaining passages either closed off or else used to
introduce additional reagents. (For example, a multi-passage nozzle
of the type described in WO-95/01221 or WO-96/00610 may be used.
Such nozzles have two or more concentric (coaxial) passages, the
outlets of which are typically separated by a short distance to
allow a small degree of internal mixing to take place between
fluids introduced through the respective passages before they exit
the nozzle. The anti-solvent could for instance be introduced
through the inner passage of such a nozzle, traversing a small
"mixing" zone as it exits that inner passage and then passing
through the main nozzle outlet into the particle formation
vessel.)
[0096] Inlet tube 23 is for introduction of the target
solution/suspension, and is so shaped and located that the
direction of flow of the solution/suspension at its outlet 24 (see
FIG. 5) will be perpendicular to that of the anti-solvent exiting
nozzle 21. Again the tube is of circular cross section.
[0097] FIG. 4 shows how tube 23 is mounted, by means of the
supporting and locking pieces 25, on a collar 26 which is itself
mounted around the lower portion of the nozzle 21. The arrangement
is such as to allow adjustment of the distance "d" between the
outlets of nozzle 21 and tube 23. It can be seen that the outlet of
tube 23 is positioned on the central longitudinal axis of the
nozzle 21.
[0098] Both the nozzle 21 and the tube 23 are preferably made from
stainless steel.
[0099] The assembly of FIGS. 3 to 5 may be less likely to suffer
blockages (at the nozzle and tube outlets) than a multi-component
SEDS.TM. nozzle of the type described in WO-95/01221, particularly
when the operating conditions are such as to allow a very rapid and
efficient removal of the solvent vehicle, from the target
solution/suspension, by the anti-solvent.
EXAMPLES
[0100] Apparatus as shown in FIG. 2, incorporating a fluid inlet
assembly as shown in FIGS. 3 to 5, was used to carry out particle
formation methods in accordance with the invention. The nozzle 21
comprised a fluid inlet tube of internal diameter 1.6 mm and an
outlet of diameter 0.2 mm. The internal bore at the end of the
inlet tube 23 was 0.125 mm. The vertical separation "d" between the
nozzle and tube outlets was varied between 0 and 8 mm, "0"
representing the situation where the solution tube 23 contacted the
lower end of the nozzle 21.
[0101] Supercritical carbon dioxide was used as the anti-solvent.
It was pumped at a flow rate (of liquid CO.sub.2, prior to passing
through a heater) of 200 g/min. Its temperature on entry into the
nozzle 21 was 356 K (83.degree. C.).
[0102] The pressure in the particle formation vessel 1 (capacity 2
litres) was maintained at 80 bar and 309-313 K (36-40.degree. C.).
The CO.sub.2 back pressure was between 250 and 300 bar. These
conditions created a sonic or supersonic CO.sub.2 velocity at the
nozzle outlet 22.
Examples A
[0103] Various target compounds were dissolved in appropriate
solvents and introduced into the apparatus via tube 23. The
distance "d" between the outlets of the anti-solvent nozzle and the
solution inlet tube was kept constant at 4 mm. Particle formation
was allowed to occur by the action of the CO.sub.2 anti-solvent,
and the products collected in the vessel 1. The products were
assessed by scanning electron microscopy (SEM) and in most cases
their particle sizes analysed using an Aerosizer.TM. and/or
Sympatec.TM. system.
[0104] The results of these experiments are shown in Table 1 below.
TABLE-US-00001 TABLE 1 Target Target solution solution Product size
Product size Target concentration flow rate (Aerosizer .TM.)
(Sympatec .TM.) Expt no. solution (% w/v) (ml/min) (.mu.m) (.mu.m)
A1 Compound I 3 4 2.84 -- in methanol A2 Compound II 1.75 4 -- 5.75
in methanol A3 Compound 3 0.5 1.39 7.99 III in DMF A4 Compound 0.85
4 -- -- IV in DMF A5 Compound 3 1 -- 4.6 V in DMSO A6 Compound 5 1
0.97 2.5 VI in THF
[0105] SEM photographs of the products of Experiments A1, A2, A5
and A6 are shown in FIGS. 6 to 9 respectively.
Examples B
[0106] In these experiments, the distance "d" between the outlets
of the anti-solvent nozzle 21 and the solution inlet tube 23 was
varied between 0 and 8 mm. In practice, the "0" separation
represented the thickness of the inlet tube wall--in other words,
as close to zero as was possible without cutting into the nozzle
wall. The target solution was 3% w/v compound I in methanol; its
flow rate into the particle formation vessel 1 was 4 ml/min.
[0107] The results are shown in Table 2 below. TABLE-US-00002 TABLE
2 Distance Product size "d" (Aerosizer .TM.) Expt no. (mm) (.mu.m)
B1 0 3.21 B2 4 2.84 B3 8 3.63
[0108] The particle size distributions (by Aerosizer.TM.) for the
products of Examples B1, B2 and B3 are shown in FIGS. 10A and 10B,
11A and 11B, and 12A and 12B respectively.
Examples C
[0109] These experiments investigated the effect of the target
solution flow rate on the product particle size. Again various
target compounds were tested, the operating conditions being as for
Examples A.
[0110] The results are given in Table 3 below. TABLE-US-00003 TABLE
3 Target Target solution solution Product size Product size Expt
concentration flow rate (Aerosizer .TM.) (Sympatec .TM.) no. Target
solution (% w/v) (ml/min) (.mu.m) (.mu.m) C1 Compound II in 0.75 2
-- 7.8 acetone C2 Compound II in 0.75 4 -- 4.75 acetone C3 Compound
IV in 0.85 1 -- -- DMF C4 Compound IV in 0.85 4 -- -- DMF C5
Compound IV in 0.85 8 -- -- DMF C6 Compound III in 3 0.5 1.39 7.99
DMF C7 Compound III in 3 1.0 1.86 7.18 DMF C8 Compound III in 3 4
18.18 10.5 DMF C9 Compound V in 1.6 1 -- 9.1 DMF(ac)* C10 Compound
V in 1.6 4 -- 42.3 DMF(ac)* C11 Compound VI in 5 1 0.97 2.5 THF C12
Compound VI in 5 4 1.18 3.0 THF *DMF(ac) = DMF acidified with 4%
v/v acetic acid
Examples D
[0111] These experiments compared two types of fluid inlet
assembly. In Example D1, a two-fluid coaxial nozzle of the type
described in WO-95/01221 was used to co-introduce supercritical
CO.sub.2 and Compound VI in solution in THF (tetrahydrofuran). The
internal diameter of the inner nozzle passage, through which the
CO.sub.2 was introduced, was 1.6 mm; that of the outer passage,
through which the target solution was introduced, 2.5 mm. The
nozzle outlet diameter was 0.2 mm.
[0112] In Example D2, an assembly of the type illustrated in FIGS.
3 to 5, with a nozzle outlet separation "d" of 4 mm, was used to
introduce the same reagents. The CO.sub.2 was introduced through
the inner passage of the nozzle used in Example D1; the outer
nozzle passage was not used.
[0113] All other operating conditions were the same for both
experiments. Within the particle formation vessel the temperature
was 309 K (36.degree. C.) and the pressure was 80 bar. The target
solution concentration was 5% w/v and its flow rate 1 ml/min. The
CO.sub.2 flow rate was 200 g/min and its inlet temperature 356 K
(83.degree. C.).
[0114] The results are given in Table 4 below. TABLE-US-00004 TABLE
4 Product size Expt (SEM) (Aerosizer .TM.) no. (.mu.m) (.mu.m) D1
1-6 .mu.m 2.54 D2 750 nm-4 .mu.m 1.5
[0115] SEMs for the products of Examples D1 and D2 are shown in
FIGS. 13 and 14 respectively. Their Aerosizer.TM. particle size
distributions are shown in FIGS. 15A and B and 16A and B
respectively, D2 showing a significantly smaller particle size and
a better distribution than D1.
[0116] It was also found that the fluid inlet assembly of FIGS. 3
to 5 (Example D2) gave a less agglomerated product.
Examples E
[0117] Two further target compounds, dihydroergotamine mesylate
(Compound VII) and ipratropium bromide (Compound VIII) were
prepared using a vessel temperature of 309 K (36.degree. C.) and
pressure of 80 bar, a CO.sub.2 flow rate of 200 g/min and a nozzle
separation "d" of 4 mm. The CO.sub.2 temperature upstream of the
vessel was 356 K (83.degree. C.). Particle sizes were assessed
using the Aerosizer.TM..
[0118] The results are shown in Table 5 below. TABLE-US-00005 TABLE
5 Target Target solution solution Product size Expt concentration
flow rate CO.sub.2 flow rate (Aerosizer .TM.) no. Target solution
(% w/v) (ml/min) (ml/min) (.mu.m) E1 Compound VII 4.0 1.0 200 6.78
in methanol E2 Compound VII 2.0 1.0 210 0.87 in methanol:water (9:1
v/v) E3 Compound VIII 1.0 2.0 210 3.79 in methanol:water (95:5 v/v)
E4 Compound VIII 1.0 4.0 210 5.62 in methanol:water (95:5 v/v)
[0119] SEM photographs of the products of Experiments E2 and E3 are
shown in FIGS. 17 and 18 respectively.
Examples F
[0120] Two drugs suitable for delivery by inhalation therapy were
produced using the method of the invention. In all cases the
products were fine, free-flowing powders having excellent
dispersibility in fluids such as in particular the propellant
fluids used to aerosolise such active substances in so-called
"metered dose inhalers". The drugs exhibited improved flocculation
performance in such propellants (in particular in HFA 134a and HFA
227ea), as compared to the performance of micronised versions of
the same drugs having comparable particle sizes.
[0121] For these experiments, the CO.sub.2 anti-solvent was pumped
at different flow rates, as shown in Table 6 below. Its temperature
on entry into the nozzle 21 of the FIG. 2 apparatus was 363 K
(90.degree. C.). The pressure in the particle formation vessel 1
(capacity 2000 ml) was maintained at 80 bar and 309 K (36.degree.
C.). The vertical separation "d" between the nozzle and solution
tube outlets was 4 mm.
[0122] The reagents, solvents and other relevant operating
conditions are summarised in Table 6, together with the particle
sizes and size distributions of the products. TABLE-US-00006 TABLE
6 Target Target Product solution solution CO.sub.2 flow MMAD
Particle Expt Target concn (% flow rate rate D (4, 3) size no.
substance Vehicle w/v) (ml/min) (ml/min) (.mu.m) spread F1
Salmeterol Methanol 3 4 158 1.7 (A) 1.8 (A) xinafoate F2
Risperidone- THF 5 4 200 3.0 (S) 1.52 (S) (9-hydroxy)- palmitate F3
Risperidone- THF 5 1 200 2.5 (S) 1.52 (S) (9-hydroxy)-
palmitate
[0123] The particle sizes quoted in Table 6 are, where indicated
(A), mass median aerodynamic diameters obtained using an
Aerosizer.TM. time-of-flight instrument and, where indicated (S),
geometric projection equivalent mass median diameters obtained
using the Helos.TM. system available from Sympatec GmbH,
Germany.
[0124] The particle size spread is defined as (D90-D10)/D50 and
indicates how narrow the size distribution may be for products made
according to the present invention.
[0125] The flocculation behaviour of the products of Examples F, in
the propellants HFA 134a and HFA 227ea, are documented in our
co-pending UK patent application no. 0208742.7.
* * * * *