U.S. patent application number 10/968481 was filed with the patent office on 2005-07-14 for process for making sterile aripiprazole of desired mean particle size.
Invention is credited to Gleeson, Margaret M., Kiang, San, Kientzler, Donald C., Kim, Soojin.
Application Number | 20050152981 10/968481 |
Document ID | / |
Family ID | 34549310 |
Filed Date | 2005-07-14 |
United States Patent
Application |
20050152981 |
Kind Code |
A1 |
Gleeson, Margaret M. ; et
al. |
July 14, 2005 |
Process for making sterile aripiprazole of desired mean particle
size
Abstract
A process is provided for making sterile aripiprazole having an
average particle size less than 100 microns but preferably greater
than 25 microns employing an impinging jet crystallization
procedure. The resulting bulk aripiprazole of desired particle size
may be used to form a sterile freeze-dried aripiprazole
formulation, which upon constitution with water and intramuscular
injection releases aripiprazole over a period of at least about one
week and up to about eight weeks.
Inventors: |
Gleeson, Margaret M.;
(Berkeley Heights, NJ) ; Kim, Soojin; (West
Orange, NJ) ; Kientzler, Donald C.; (Hightstown,
NJ) ; Kiang, San; (Madison, NJ) |
Correspondence
Address: |
STEPHEN B. DAVIS
BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT
P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Family ID: |
34549310 |
Appl. No.: |
10/968481 |
Filed: |
October 19, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60513886 |
Oct 23, 2003 |
|
|
|
Current U.S.
Class: |
424/489 |
Current CPC
Class: |
B01D 9/0009 20130101;
A61J 3/02 20130101; B01D 9/005 20130101; B01J 2/06 20130101; B01D
9/0081 20130101; B01D 9/0054 20130101; C07D 215/227 20130101; B01D
9/0063 20130101; B01D 9/0009 20130101; B01D 9/005 20130101; B01D
9/0063 20130101; B01D 9/0009 20130101; B01D 9/005 20130101 |
Class at
Publication: |
424/489 |
International
Class: |
A61K 009/14 |
Claims
What is claimed is:
1. A process for preparing sterile crystalline aripiprazole of
desired small particle size and narrow particle size distribution,
which comprises: (a) providing a jet stream of a solution of
aripiprazole in an organic solvent; (b) providing a jet stream of
anti-solvent which is capable of initiating precipitation of
aripiprazole from solution; (c) causing the jet stream of solution
of aripiprazole in solvent and the jet stream of anti-solvent to
strike each other and impinge on one another to create high
turbulence at their point of impact, each jet stream having
sufficient linear velocity to achieve high intensity micromixing of
each stream prior to nucleation, to produce a slurry of crystals of
aripiprazole monohydrate; and (d) recovering crystals of
aripiprazole monohydrate of desired small particle size and narrow
particle size distribution.
2. The process as defined in claim 1 wherein the crystals of
aripiprazole monohydrate produced have an average particle size
less than 100 microns but greater than 25 microns.
3. The process as defined in claim 2 wherein at least 95% of the
crystals of aripiprazole monohydrate produced have a particle size
of less than 100 microns.
4. The process as defined in claim 1 wherein the crystals of
aripiprazole monohydrate produced have an average particle size of
less than 25 microns.
5. The process as defined in claim 1 further including the step of
providing ultrasonic energy in the immediate vicinity of said
impinging jet streams, so as to effect nucleation and the direct
production of small crystals of aripiprazole.
6. The process as defined in claim 1 wherein the jet stream of the
solution of aripiprazole in an organic solvent is heated at a
desired elevated temperature and the jet stream of anti-solvent is
at a desired temperature below the temperature of the other jet
stream.
7. The process as defined in claim 1 wherein the organic solvent
for the aripiprazole is ethanol methanol, ethyl acetate, acetone,
acetonitrile, acetic acid or isopropyl alcohol, or mixtures of one
or more thereof, or mixtures with water.
8. The process as defined in claim 1 wherein the organic solvent
for the aripiprazole is ethanol or a mixture of ethanol and
water.
9. The process as defined in claim 1 wherein the anti-solvent is
water.
10. The process as defined in claim 1 wherein the volumetric ratio
of solution of aripiprazole in organic solvent to anti-solvent is
within the range from about 0.5:1 to about 1.5:1.
11. The process as defined in claim 1 wherein the
aripiprazole-solvent stream and the anti-solvent stream are in
about a 1:1 volume ratio.
12. The process as defined in claim 1 wherein the organic solvent
comprises ethanol and the solution of aripiprazole in ethanol is
heated at a temperature within the range from about 70 to about
85.degree. C.
13. The process as defined in claim 1 wherein the anti-solvent is
water at a temperature within the range from about 2 to about
40.degree. C.
14. The process as defined in claim 1 wherein the jet stream of a
solution of aripiprazole in organic solvent and the jet stream of
anti-solvent impinge each other at a flow rate of each which is the
same or different but is within the range from about 0.2 to about
0.3 kg/min where jet nozzles of 0.02 inch internal diameter are
employed.
15. A process for preparing sterile aripiprazole of desired small
particle size and narrow size distribution, which comprises: (a)
providing a jet stream of a solution of aripiprazole in
ethanol/water heated at a temperature within the range from about
70 to about 85.degree. C.; (b) providing a jet stream of deionized
water which is at a temperature within the range from about 2 to
about 40.degree. C.; (c) causing the jet stream of solution of
aripiprazole in ethanol and the jet stream of water each at a flow
rate within the range from about 0.2 to about 0.3 kg/min, where jet
nozzles of 0.02 inch internal diameter are employed, to impinge on
one another to create high turbulence at their point of impact to
achieve high intensity micromixing of each stream prior to
nucleation, to form a slurry of crystals of aripiprazole
monohydrate; and (d) recovering crystals of aripiprazole
monohydrate having an average particle size about 95% less than 100
microns.
16. The process as defined in claim 15 wherein the crystals of
aripiprazole recovered has an average particle size of about 95%
less than about 25 microns.
17. The process as defined in claim 15 further including the step
of providing ultrasonic energy in the immediate vicinity of said
impinging jet streams, so as to effect nucleation and the direct
production of small crystals of aripiprazole.
18. The process as defined in claim 15 wherein the aripiprazole has
a low pyrogen content and is the anhydrous form of aripiprazole or
the monohydrate form of aripiprazole.
19. The process as defined in claim 15 wherein the
aripiprazole-ethanol solution contains from about 0.01 to about 0.1
kg/L aripiprazole.
20. The process as defined in claim 15 wherein the stream of
solution of aripiprazole and the stream of water are each
sterilized.
21. The process as defined in claim 15 wherein the stream of
aripiprazole in ethanol and the stream of deionized water flow in
opposite directions and form a plane when they impinge one another,
and strike each other to cause rapid homogeneous mixing and
supersaturation due to high turbulence and high intensity of
micromixing upon impact, which initiates rapid nucleation.
22. The process as defined in claim 15 wherein average crystal size
decreases with increasing concentration of aripiprazole in ethanol
and supersaturation and decreasing temperature of the
anti-solvent.
23. The process as defined in claim 15 wherein the
aripiprazole-ethanol stream and the water stream are in about a 1:1
volume ratio with each other.
Description
FIELD OF THE INVENTION
[0001] This application claims a benefit of priority from U.S.
Provisional Application No. 60/513,886, the entire disclosure of
which is herein incorporated by reference.
[0002] The present invention related to a process for making
sterile aripiprazole of desired particle size distribution and mean
particle size which is especially adapted for use in preparing a
controlled release formulation which releases aripiprazole over at
least one week or more.
BACKGROUND OF THE INVENTION
[0003] U.S. provisional application No. 60/513,618, discloses a
controlled release sterile injectable aripiprazole formulation in
the form of a sterile suspension, and a method for preparing a
sterile freeze-dried aripiprazole formulation (employed in forming
the injectable formulation) which includes the steps of:
[0004] (a) preparing sterile bulk aripiprazole preferably having a
desired particle size distribution and mean particle size within
the range from about 5 to about 100 microns, more preferably from
about 10 to about 90 microns,
[0005] (b) preparing a sterile vehicle for the sterile bulk
aripiprazole,
[0006] (c) combining the sterile bulk aripiprazole and the sterile
vehicle to form a sterile primary suspension,
[0007] (d) reducing the mean particle size of aripiprazole in the
sterile primary suspension to within the range from about 0.05 to
about 30 microns, to form a final sterile suspension, and
[0008] (e) freeze drying the final sterile suspension to form a
sterile freeze-dried suspension of the aripiprazole of desired
polymorphic form (anhydrous, monohydrate, or a mixture of
both).
[0009] In carrying out the above method for preparing the
freeze-dried aripiprazole formulation, it is required that
everything be sterile so that sterile aripiprazole and sterile
vehicle are combined aseptically to form a sterile suspension and
that the sterile suspension be freeze-dried in a manner to form
sterile freeze-dried powder or cake. Thus, an aseptic procedure is
employed to produce sterile bulk aripiprazole of desired mean
particle size, and particle size distribution, by crystallization
methods as opposed to ball milling. The sterile bulk aripiprazole
preferably prepared in step (a) by means of the impinging jet
crystallization method, has a desired small particle size and
narrow particle size distribution, high surface area, high chemical
purity, and high stability due to improved crystal structure.
[0010] The impinging jet crystallization utilizes two jet streams
that strike each other head-on. One of the streams carries a
solution rich in the aripiprazole and the other carries an
anti-solvent, such as water. The two streams strike each other
which allows for rapid homogeneous mixing and supersaturation due
to high turbulence and high intensity of micromixing upon impact.
This immediate achievement of supersaturation initiates rapid
nucleation. In general, the average crystal size of the
aripiprazole decreases with increasing supersaturation and
decreasing temperature of the anti-solvent. Therefore, in order to
obtain the smallest particle size, it is advantageous to have the
highest possible concentration of the aripiprazole rich solution
and the lowest temperature of the anti-solvent.
[0011] The technique employed for forming sterile bulk aripiprazole
is important since particle size of the aripiprazole formulation
controls its release profile in the blood system over a period of
one month.
[0012] It has been found that batch crystallization of aripiprazole
produces particles .gtoreq.100 microns. However, in formulating the
controlled release sterile aripiprazole injectable formulation
discussed above, the particle size of the aripiprazole needs to be
95%.ltoreq.100 microns. In addition, a narrow particle size
distribution is needed to maintain control of the release profile.
Milling of batch aripiprazole is undesirable, as a broad particle
size distribution will be obtained. Thus, it would be advantageous
to employ a technique for preparing sterile bulk aripiprazole which
can reduce particle size of aripiprazole to 95%.ltoreq.100 microns
with a narrower particle size distribution than attainable
employing batch crystallization.
[0013] U.S. Pat. No. 5,006,528 to Oshiro et al. discloses
7-[(4-phenylpiperazino)-butoxy] carbostyrils, which include
aripiprazole, as dopaminergic neurotransmitter antagonists.
[0014] Aripiprazole which has the structure 1
[0015] is an atypical antipsychotic agent useful in treating
schizophrenia. It has poor aqueous solubility (<1 .mu.g/mL at
room temperature).
[0016] U.S. Pat. No. 6,267,989 to Liversidge, et al. discloses a
method for preventing crystal growth and particle aggregation in
nanoparticulate compositions wherein a nanoparticulate composition
is reduced to an optimal effective average particle size employing
aqueous milling techniques including ball milling.
[0017] U.S. Pat. No. 5,314,506 to Midler, et al. discloses a
process for the direct crystallization of a pharmaceutical having
high surface area particles of high purity and stability wherein
impinging jet streams are employed to achieve high intensity
micromixing of particles of the pharmaceutical followed by
nucleation and direct production of small crystals.
[0018] U.S. Pat. No. 6,302,958 to Lindrud et al. discloses a method
and apparatus for crystallizing submicron-sized crystals of a
pharmaceutical composition employing sonication to provide
ultrasonic energy in the immediate vicinity of impinging fluid drug
and solvent streams so as to effect nucleation and the direct
production of small crystals.
[0019] U.S. application Ser. No. 10/419,418, filed Apr. 21, 2003 by
Chenkou Wei (attorney docket TU58 NP) which is based on U.S.
Provisional Applications Nos. 60/376,414, filed Apr. 29, 2002 and
60/439,066, filed Jan. 9, 2003 entitled "Crystallization System
Using Atomization" discloses a method for crystallizing a
pharmaceutical by atomizing one solution and introducing the
atomized solution into a vessel containing a second solution where
the solutions are mixed to form a product, which does not require
post-crystallization milling. This application is incorporated
herein by reference.
[0020] U.S. application Ser. No. 10/419,647, filed Apr. 21, 2003 by
Chenkou Wei (attorney docket TU59 NP) which is based on U.S.
Provisional Applications Nos. 60/379,351, filed May 10, 2002 and
60/439,057, filed Jan. 9, 2003 entitled "Crystallization System
Using Homogenization" discloses a process for crystallizing a
chemical material from a first solution and a second solution
wherein the first solution is atomized and introduced into a second
solution, and the atomized solution and second solution are mixed
to form the product. This application is incorporated herein by
reference.
BRIEF DESCRIPTION OF THE INVENTION
[0021] In accordance with the present invention, there is provided
a process for preparing sterile bulk aripiprazole of desired small
particle size and narrow particle size distribution, preferably
having an average particle size less than about 100 microns but
preferably greater than 25 microns, which includes the steps
of:
[0022] (a) providing a jet stream of a solution of aripiprazole in
an organic solvent, preferably ethanol, preferably heated at a
desired elevated temperature;
[0023] (b) providing a jet stream of anti-solvent, preferably
water, which is capable of initiating precipitation of aripiprazole
from solution, preferably said anti-solvent being at a desired
temperature below the temperature of the solution of
aripiprazole;
[0024] (c) causing the jet stream of solution of aripiprazole in
solvent and the jet stream of anti-solvent to strike each other and
impinge on one another to create high turbulence at their point of
impact, each jet stream having sufficient linear velocity to
achieve high intensity micromixing of each stream prior to
nucleation, to produce a slurry of crystals of aripiprazole
monohydrate; and
[0025] (d) recovering crystals of aripiprazole monohydrate of
desired small particle size and narrow particle size
distribution.
[0026] Prior to step (d) ultasonic energy may be provided, by means
of a sonication probe, as described in U.S. Pat. No. 6,302,958, the
disclosure of which is incorporated herein by reference, the tip of
which is positioned within a gap defined between the two jet
streams, to cause the impinging jet streams to achieve high
intensity micromixing of fluids prior to nucleation.
[0027] In addition, in accordance with the present invention, a
preferred process is provided for preparing sterile bulk
aripiprazole of desired average particle size of less than about
100 microns, but preferably greater than 25 microns, and narrow
particle size distribution, which includes the steps of:
[0028] (a) providing a jet stream of a solution of aripiprazole in
ethanol heated at a temperature within the range from about 70 to
about 85.degree. C., preferably from about 75 to about 80.degree.
C.;
[0029] (b) providing a jet stream of deionized water which is at a
temperature within the range from about 2 to about 40.degree. C.,
preferably from about 20 to about 35.degree. C.;
[0030] (c) causing the jet streams of solution of aripiprazole and
water, each at a flow rate (where jet nozzles of 0.02 inch internal
diameter are employed) within the range from about 0.20 to about
0.30 kg/min, preferably from about 0.22 to about 0.28 kg/min, to
impinge on one another to create high turbulence at their point of
impact to achieve high intensity micromixing of each stream prior
to nucleation, and form a slurry of crystals of aripiprazole
monohydrate; and
[0031] (d) recovering crystals of aripiprazole monohydrate having
an average particle size less than 100 microns, but preferably
greater than 25 microns, preferably about 95% of the crystals
having a particle size less than 100 microns.
[0032] Prior to step (d) ultasonic energy may be provided, by means
of a sonication probe, as described above, the tip of which is
positioned within a gap defined between the two jet streams, to
cause the impinging jet streams to achieve high intensity
micromixing of fluids prior to nucleation.
[0033] In carrying out the above process of the invention, the
volumetric ratio of solution of aripiprazole in organic solvent to
anti-solvent is within the range from about 0.5:1 to about 1.5:1,
preferably from about 0.9:1 to about 1.1:1.
[0034] The above processes may also be employed to prepare crystals
of aripiprazole monohydrate having an average particle size of less
than 25 microns.
[0035] The processes of the invention as described above employs
jet streams which impinge on each other to achieve high intensity
micromixing of the streams to enable formation of a homogeneous
composition prior to the start of nucleation in a continuous
crystallization process. Nucleation and precipitation are initiated
utilizing the effect of antisolvent addition on the solubility of
the aripiprazole in the solvent therefor.
[0036] The sonication steps disclosed above are carried out as
described in U.S. Pat. No. 6,302,958.
[0037] The aripiprazole produced by the process of the invention
may be employed in forming sterile bulk aripiprazole having a
desired particle size distribution, preferably 10%<10 microns,
50%<35 microns and 95%<100 microns, and mean particle size
within the range from about 25 to about 100 microns.
[0038] The sterile bulk aripiprazole prepared by the process of the
invention may be used in forming a sterile-freeze dried
aripiprazole formulation which may be suspended in water to form an
injectable aripiprazole formulation as described in U.S.
provisional Application No. 10/419,647.
[0039] Each of the above embodiments of the process of the
invention are referred to as the impinging jet crystallization
process of the invention.
[0040] The process of the invention employs impinging jet
crystallization technology, an example of which is disclosed in
U.S. Pat. No. 5,314,506 to Midler et al.
[0041] It will also be appreciated that the sterile bulk
aripiprazole of desired small particle size and narrow particle
size distribution as described above may be prepared employing the
process and apparatus described and claimed in each of the Chendou
Wei applications entitled "Crystallization System Using
Atomization" and "Crystallization System Using Homogenization"
described above and incorporated herein by reference.
BRIEF DESCRIPTION OF THE FIGURES
[0042] The accompanying FIGURE is a schematic representation of an
impinging jet crystallization process flow diagram used in carrying
out the process of the invention, which includes a crystallizer
vessel.
DETAILED DESCRIPTION OF THE INVENTION
[0043] The process of the invention is illustrated in the following
reaction scheme: 2
[0044] In carrying out the process of the invention, low pyrogen
aripiprazole starting material is employed to ensure that the
sterile aripiprazole of desired particle size will be produced. The
low pyrogen aripiprazole starting material may be either the
anhydrous form or the monohydrate form. Either material will yield
the desired monohydrate form from the impinging jet crystallization
process of the invention.
[0045] The process of the invention employs two jet nozzles to
create two impinging jet streams to achieve high intensity
micromixing of the streams prior to nucleation and formation of
crystals of aripiprazole monohydrate. The two impinging jet streams
should be substantially diametrically opposed to one another with
the nozzles directed to face each other. The jet nozzles will be
aligned and positioned so that the fluid streams will impact
head-on and will impinge. When the jet nozzles are properly aligned
and appropriate flow rates chosen, the two streams will form a
plane when impinged.
[0046] Each of the process streams, namely the aripiprazole-organic
solvent stream and the anti-solvent stream will be sterilized. To
sterilize the two process streams, both streams are preferably
polish filtered and then sterile filtered through an appropriate
size filter, such as a 0.2 micron filter. The aripiprazole stream
should be filtered at an elevated temperature, for example, about
80.degree. C., to prevent precipitation.
[0047] The temperature and composition of each solution are chosen
so that 1) no material will crystallize upstream of the impinging
jets, and, 2) sufficient supersaturation will be developed in the
impinging jets to cause nucleation. Micromixing creates temperature
and compositional uniformity throughout the mixture prior to the
start of nucleation.
[0048] To obtain the smallest particle size of aripiprazole, the
highest possible concentration of aripiprazole in the organic
solvent should be employed. Thus, the starting solution of
aripiprazole in organic solvent, preferably ethanol, will contain
from about 0.01 to about 0.1 kg/L aripiprazole, preferably from
about 0.04 to about 0.06 kg/L aripiprazole. In a most preferred
embodiment, the aripiprazole will be present in an amount of about
0.05 kg/L.
[0049] The organic solvent will preferably be ethanol, most
preferably from about 92 to about 97% ethanol, with the remainder
being water.
[0050] Other organic solvents, such as methanol, ethyl acetate,
acetone, acetonitrile, acetic acid or isopropyl alcohol or mixtures
of two or more thereof, or mixtures with water may be employed.
[0051] The anti-solvent will preferably be deionized water.
[0052] The two streams, namely, the stream of the solution of
aripiprazole in the organic solvent and the stream of anti-solvent,
are characterized as jet streams in that they will be made to
strike each other head on at high linear velocities with a minimum
of 5 m/s. The flow rates will be determined by the diameter of the
jet nozzles employed to deliver the streams and the rate at which
the streams are pumped through the nozzles. In a preferred
embodiment, the flow rate of each of the stream of
aripiprazole/solvent and the stream of antisolvent will be
essentially the same, but will of course be in opposite
directions.
[0053] The flow rates will be chosen so that proper impinging is
achieved. For example, where jet nozzles of 0.02 inch internal
diameter are employed, flow rates will be within the range from
about 0.20 to about 0.30 kg/min, preferably from about 0.22 kg/min
to about 0.28 kg/min, more preferably from about 0.24 kg/min to
about 0.26 kg/min, and optimally about 0.25 kg/min.
[0054] The temperature of each of the streams is important in
determining ultimate size of the particles of aripiprazole
produced. Thus, the aripiprazole-solvent (preferably ethanol)
stream should be heated at a temperature within the range from
about 70 to about 85.degree. C., preferably from about 75 to about
80.degree. C. The anti-solvent stream (preferably water) should be
at a temperature substantially less than the temperature of the
aripiprazole-solvent stream, and within the range from about 2 to
about 40.degree. C., preferably from about 20 to about 35.degree.
C., and optimally about 30.degree. C.
[0055] The two streams strike each other head-on, from opposite
directions, to cause rapid homogeneous mixing and supersaturation
due to high turbulence and high intensity of mixing upon impact.
The immediate achievement of supersaturation initiates rapid
nucleation. In general, the average crystal size decreases with
increasing supersaturation and decreasing temperature of the
anti-solvent. The smallest particle size of aripiprazole is
obtained employing the highest possible concentration of the
aripiprazole solution and the lowest temperature of the
anti-solvent. Sonication is utilized where even smaller particles
are desired.
DESCRIPTION OF THE FIGURE
[0056] Referring to the accompanying FIGURE, an impinging jet
crystallization process flow diagram and crystallizer vessel used
in carrying out the process of the invention are shown which
includes a jacketed impingement crystallization vessel 10. There
are two jacketed-vessels 12, 14 that flank the impingement vessel
10 to the left and right which contain the aripiprazole-rich
solution (12) and the anti-solvent (14), respectively. Both of
these side vessels 12, 14 are spaced apart from the impingement
vessel 10. Impinging jet nozzles 16, 18, each having a 0.02-inch
diameter, are spaced 10 mm apart. The impingement vessel 10 may
include agitator 11 and a sonicator (as employed in U.S. Pat. No.
6,302,958), if desired, not shown for drawing clarity. Outlet 31 of
impingement vessel 10 is connected to receiving vessel 32, via line
33. Overflow line 35 links impingement vessel 10 and line 33 and
aids in maintaining a constant volume in impingement vessel 10.
[0057] The above description is of the sterile portion of the flow
diagram. The non-sterile portion as shown includes a vessel 34 for
holding a solution of aripiprazole in ethanol, preferably 95%
ethanol, which is pumped via pump 36 through polish filter 38 and
sterile filter 40 into vessel 12 and processed as described
above.
[0058] The jet nozzles 16, 18 should be placed so that the fluid
streams they emit will impinge, inside the stirred impingement
vessel 10 or inside a separate jet chamber (not shown) which is
linked directly to the vessel 10. The fluid jets must impinge to
create an immediate high turbulence impact. The two jet nozzles are
preferably arranged so that they are substantially diametrically
opposed to each other with their outlet tips directed to face each
other; i.e., the two jet nozzles are at or close to a 180 degree
angle to each other from an overhead view. Preferably, each jet
outlet nozzle can have a slight downward angle from the horizontal,
for example, about 10 degrees, to help the flowing material move
down and out of the chamber.
[0059] Likewise, two jet nozzles placed directly inside the stirred
impingement vessel 10 are preferably arranged so that they are
substantially diametrically opposed to each other with their outlet
tips directed to face each other. When the jet nozzles are so
placed, each nozzle can have a slight upward or downward angle from
the horizontal of from 0 degrees up to about 15 degrees, but
preferably the two nozzles have just enough downward angle from the
horizontal (ca. 13 degrees) to ensure that the fluid stream of one
will not enter the outlet hole of the opposite nozzle.
[0060] Jet nozzle 16 is used to transport aripiprazole solution
into the vessel 10 (or separate jet chamber) and the other jet 18
is used to similarly transport water. The distance between the
nozzle tips inside the jet chamber or vessel 10 should be such that
the hydro-dynamic form of each fluid jet stream remains essentially
intact up to the point of impingement. Therefore, the maximum
distance between the nozzle tips will vary depending on the linear
velocity of the fluids inside the jet nozzles. To obtain good
results for generally non-viscous fluids, linear velocity in the
jet nozzles should be at least about 5 meters/sec., more preferably
above 10 meters/sec., and most preferably between about 20 to 25
meters/sec., although the upper limit of linear velocity is only
limited by the practical difficulties involved in achieving it.
Linear velocity and flow rate can both be controlled by various
known methods, such as altering the diameter of the entry tube
and/or that of the nozzle outlet tip, and/or varying the strength
of the external force that moves the fluid into and through the
nozzle. Each jet apparatus can be manipulated independently to
attain a desired final fluid composition ratio. When the desired
flow ratio of one jet to the other differs from unity, preferably
the difference is compensated for by appropriate sizing of the
entry tubes. For example, if a 4:1 volumetric ratio of feed
solution to anti-solvent is desired, the entry tube delivering feed
solution should be twice the diameter of the entry tube delivering
anti-solvent. When the jet streams impinge inside a jet chamber,
residence time for the fluid inside the jet chamber is typically
very short, i.e., less than ten seconds.
[0061] Stirring in the vessel is provided by standard agitators 11,
preferably Rushton 10 turbines, Intermig impellers, or other
agitators suitable for stirring a slurry suspension. Any impeller
providing good circulation inside the vessel may be used. However,
when the jet streams are arranged to impinge directly inside the
stirred vessel, an agitator that does not interfere with the space
occupied by the impinging jet streams inside the vessel is
preferred, especially, e.g., a Rushton turbine. Impinging jet
streams inside the vessel are most preferably placed in the
effluent stream of the agitator, and the height of the liquid in
the stirred vessel 10 when operated in continuous mode (i.e., flow
in equals flow out, constant volume maintained), is most preferably
between about two to four times the height of the impeller.
[0062] The crystallization is preferably run in a continuous
process and the appropriate residence time for the completion of
crystal digestion is attained by adjusting the volume capacity of
the stirred vessel, but the mixture can be held up in the vessel
for any desired length of age time if batchwise processing is
desired.
[0063] Manual seeding can be done at any point in the system, e.g.,
in the stirred vessel 10, the transfer line or the jet chamber
itself. In some situations, the continuous jet process may be
"self-seeding", i.e., the first crystals to form inside the jet
chamber (if used), the transfer line (if used) or the stirred
vessel 10 serve as seed for the material that flows through
thereafter.
[0064] The micromixed material must be highly supersaturated to
attain the beneficial results of the jet crystallization process.
Aside from thermoregulated initiation of nucleation, temperature
variation also affects product results when anti-solvent is used to
initiate nucleation because of its effect on supersaturation.
Generally, good results can be achieved using a volumetric ratio of
aripiprazole to anti-solvent that provides a high degree of
supersaturation in the jet chamber in a temperature range of about
24.degree. C. to 70.degree. C., although the temperature upper
limit is limited only by the chosen solvent's boiling point.
[0065] An example of the impingement vessel which may be employed
is disclosed in U.S. Pat. No. 5,314,506 to Midler et al. and in
U.S. Pat. No. 6,302,958 to Lindrud et al. which are incorporated
herein by reference.
[0066] To prepare a 100-gram batch of aripiprazole monohydrate, a
100 grams of aripiprazole anhydrous N1 is charged into a 4-L vessel
12 and dissolved in 2 L of 95% ethanol at 75 to 80.degree. C. The
clear solution is then transferred to the product-rich 2-L jacketed
vessel 10 and maintained at 75 to 80.degree. C. In the anti-solvent
vessel 14, 2 L of deionized (DI) water is then charged and heated
to 28 to 32.degree. C. When both liquids are at the desired
temperatures, the two streams are pumped simultaneously via pumps
20 and 22 through mass flow meters 24, 26, respectively, and
sterile filters 28, 30, respectively, through the 0.02-inch
internal diameter nozzles 16, 18 and impinge at a rate of 0.22 to
0.28 kg/min to produce the monohydrate crystals. The crystals are
continuously transferred to receiving vessel 32 to maintain a
constant volume in the impingement vessel 10. It takes
approximately 5 to 7 minutes to impinge a 100-gram batch. The
slurry is cooled to 20 to 25.degree. C., filtered, and washed with
200 mL of deionized water. The cake is then dried at 35.degree. C.
under vacuum to obtain approximately 100 grams of aripiprazole
monohydrate, H0, with a Karl Fisher % (KF%) of ca. 4% w/w.
EXAMPLES
[0067] The following working Examples represent preferred
embodiments of the present invention.
Example 1
[0068] Sterile bulk active pharmaceutical ingredient (API)
aripiprazole was prepared using impinging crystallization with
sonication employing an apparatus set up as shown in the attached
Figure.
[0069] The following procedure was employed to form a sterile bulk
aripiprazole.
[0070] 1. Charge 100 g of aripiprazole in a 4 L flask 34.
[0071] 2. Add 2 L of 95% ethanol.
[0072] 3. Heat the suspension to 80.degree. C. until it becomes a
clear solution.
[0073] 4. Transfer the hot aripiprazole solution to a 2 L jacketed
vessel 12 and maintain at 75-80.degree. C.
[0074] 5. Charge 2 L of deionized (DI) water to a 2 L jacketed
vessel 14.
[0075] 6. Cool the DI water to 2.degree. C.
[0076] 7. Add 100 mL of 95% ethanol and 100 mL of DI water to the
impinging vessel 10 and cool to 2.degree. C.
[0077] 8. Initiate sonication (Sonication is provided by a 0.5 inch
probe with 120 W power output employed as described in U.S. Pat.
No. 6,302,958).
[0078] 9. Pump the aripiprazole solution through a 0.02 inch
diameter nozzle 16 at 0.25 kg/min and impinge it with the 2.degree.
C. water pumped at 0.25 kg/min through a 0.02 inch diameter nozzle
18.
[0079] 10. Sonicate the newly formed crystal slurry in the impinge
vessel 10 while continuously transferring the crystals to a
receiving vessel 32 to maintain a constant volume in the
impingement vessel 10.
[0080] 11. Cool the slurry to 20 to 25.degree. C. at the end of
impingement.
[0081] 12. Filter the slurry.
[0082] 13. Wash the cake with 200 mL of DI water.
[0083] 14. Dry the wet cake at 35.degree. C. under vacuum to obtain
97.9 g of aripiprazole with a KF of 4.0% w/w, with reduced particle
size (95% <100 microns).
Example 2
[0084] Sterile bulk API aripiprazole was prepared using impinging
jet crystallization and an apparatus set up as shown in the
accompanying figure.
[0085] The following procedure was employed to form a sterile bulk
aripiprazole:
[0086] 1. Suspend 100 g of aripiprazole in 2000 mL of 95% ethanol.
Heat the suspension to 80.degree. C. until it becomes a clear
solution.
[0087] 2. Polish filter the aripiprazole solution into a holding
vessel 12 and maintain at 80.degree. C.
[0088] 3. Polish filter 2000 mL water to another holding vessel 14
and heat to 80.degree. C.
[0089] 4. Pump the aripiprazole solution through a 0.02 inch
diameter nozzle 16 at 0.25 kg/min and impinge it with the
30.degree. C. water pumped at 0.25 kg/min through a 0.02 inch
diameter nozzle 18 to form a crystal slurry which is collected in
an impingement vessel 10.
[0090] 5. Agitate the newly formed crystal slurry in the
impingement vessel 10 while continuously transferring it to a
receiver 32 to maintain a constant volume in the impingement vessel
10.
[0091] 6. At the end of impingement, cool the slurry in the
receiver 32 to room temperature.
[0092] 7. Filter the slurry.
[0093] 8. Dry the wet cake at 35.degree. C .under vacuum to
yielding 100 g (96% recovery) of aripiprazole with reduced particle
size (95%<100 microns).
Example 3
[0094] An aripiprazole injectable aqueous suspension (200 mg
aripiprazole/2 mL, 200 mg/vial) was prepared as follows.
[0095] The following ingredients were added to a 3L glass jacketed
vessel maintained at 15.degree. C. (.+-.5.degree. C.) to form a
sterile primary suspension:
1 Aripiprazole (prepared by impinging jet 100 g crystallization as
described in Example 2): Carboxymethylcellulose, Sodium Salt 7L2P
9.0 g Mannitol 45 g Sodium Phosphate, Monobasic 0.8 g Sodium
Hydroxide Solution, 1N q.s. to adjust pH to 7.0 Water, USP q.s. to
1000 g
[0096] The sterile suspension was mixed at 500-1000 rpm for about
0.5 hour and then at 300-500 rpm for an additional 1 hour under 20
"Hg (+5"Hg) vacuum.
[0097] 2.5 mL of the above suspension were aseptically filled into
sterilized vials which were then aseptically partially stoppered
with sterilized stoppers. The vials were aseptically transferred to
a freeze dryer and lyophilized according to the following
cycle:
[0098] (a) thermal treatment: freeze product at -40.degree. C. over
0.1-1 h and keep at -40.degree. C. for at least 6 h,
[0099] (b) cool the condenser to -50.degree. C. or below,
[0100] (c) primary drying: lower chamber pressure to approximately
100 microns Hg and increase product temperature to -5.degree. C.
over approximately 2 h; continue primary drying at -5.degree. C.
and 100 microns Hg for at least 48 h,
[0101] (d) stopper the vials under atmospheric pressure or partial
vacuum using sterile nitrogen or air and remove from the freeze
dryer,
[0102] (e) seal the vials with the appropriate seals and label.
* * * * *