Note: Descriptions are shown in the official language in which they were submitted.
TITLE: DIRECT PROBE SENSED TEMPERATURE METHOD FOR SPEED
CHANGE FOR HEAT SENSITIVE PORTIONS OF A THERMOKINETICALLY MELT
BLENDED BATCH
10
BACKGROUND OF THE INVENTION
1. FIELD OF THE INVENTION
The present disclosure relates in general to the field of pharmaceutical
manufacturing, and more particularly, to thermokinetic mixing of active
pharmaceutical ingredients (APIs) to produce novel dosage forms.
2. BACKGROUND
Current high-throughput molecular screening methods used by the
pharmaceutical industry have resulted in a vast increase in the proportion of
newly
discovered molecular entities which are poorly water-soluble. The therapeutic
potential of many of these molecules is often not fully realized either
because the
molecule is abandoned during development due to poor pharmacokinetic profiles,
or
because of suboptimal product performance. Also, in recent years the
pharmaceutical industry has begun to rely more heavily on formulational
methods for
improving drug solubility owing to practical limitations of salt formation and
chemical
modifications of neutral or weakly acidic/basic drugs. Consequently, advanced
formulation technologies aimed at the enhancement of the dissolution
properties of
poorly water-soluble drugs are becoming increasingly more important to modern
drug delivery.
U.S. Pat. No. 8,486,423, naming the same inventor as this application and
additional co-inventors, is directed to the application of thermokinetic
compounding
in the field of pharmaceutical manufacturing. Thermokinetic compounding or
"TKC"
is a method of thermokinetic mixing until melt blended. A pharmaceutical
composition or composite made by thermokinetic compounding may be further
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'
processed according to methods well known to those of skill in the field,
including
but not limited to hot melt extrusion, melt granulation, compression molding,
tablet
compression, capsule filling, film-coating, or injection molding into a final
product
Although the application of thermokinetic compounding in the field of
pharmaceutical manufacturing offers significant advantages over other
methodologies known in the pharmaceutical arts, the process for continuously
melt
blending certain heat sensitive or thermolabile components using a
thermokinetic
mixer may be improved in certain cases. Blending such a combination of
components can require using an elevated shaft speed or a reduced shaft speed
for
.. an extended processing time sufficient to impart complete amorphosity on
the fully
processed batch. It has been found in certain cases that such processing may
result in an exceedance of a limit temperature or heat input, which may result
in
degradation of the thermolabile components. It appears that the substantial
amount
of heat absorbed by the entire batch may result in thermal degradation of
.. thermolabile components instead of increasing overall batch temperature.
Substantially complete amorphosity is a measure well-known in the art of
pharmaceutical preparation and processing; bioavailability may be impaired in
compositions lacking substantially complete amorphosity.
BRIEF SUMMARY OF THE INVENTION
The present disclosure continues efforts at research and development
relating to the application of thermokinetic compounding to production of
pharmaceutical composites and compositions. A short description of the basic
physical processing of pharmaceutical components that are introduced as a
batch
into the thermokinetic mixing chamber of a thermokinetic mixer will help one
.. understand this process.
The thermokinetic mixer is entirely unique in the world of process equipment.
Heating during the mixing action arises from the process materials themselves
(without chemical reaction, per se, although intending for crystalline
pharmaceuticals
a structure change), without external heat exchange, such as indirect heat
transfer
.. by radiation or convection or even direct heating, such as by way of direct
flame
contact. Thermokinetic mixers have proprietary extensions extending from a
drive
shaft, where that drive shaft extends through an axis of the cylindrical
mixing
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chamber. These proprietary extensions are formed so as to provide an angled
contact surface oriented in the direction of the angular drive direction,
where the
angled contact surface is adapted to reduce or eliminate fracturing, tearing
or
breaking of process component molecules. The process steps occurring within
the
thermokinetic mixer during processing are generally:
1. a controlled sliding, friction-heating contact occurring between a
process component particle and the extension contact surface, whereby high
transient temperatures are generated at the contact side(s) (plural of "side"
because the particle can roll as well as slide across the contact surface,
resulting in heated sides) of the process component particle;
2. before the local, high transient temperature can adversely affect the
chemical composition of the extension-heated process component particle, it
is ejected angularly away from the contact surface of the extension, thereby
(because of the extremely turbulent conditions within the mixing chamber)
resulting in instant, cooling contact with mixing chamber air and other
process
component particles, resulting in instant distribution to essentially the
entire
batch of process component particles of heat generated by the previous
sliding, friction-heating contact;
3. the angularly deflected particles are abrade each other, generating an
instantly diffused heating and, where meltable particles have reached a
melting temperature, molten particles join and pull apart with captured non-
molten particles, resulting in extremely comminuted or molecularly-dispersed
non-molten particles uniformly distributed within the molten particles;
4. the angularly deflected particles are also directed axially and
angularly
outward from the drive shaft, resulting in sliding, friction-heating and
somewhat tangential contact with the inside surface of the cylindrical mixing
chamber, whereby high transient temperatures are generated at the contact
side of the process component particle, so that, as the particle loses kinetic
energy from its contact (direct or indirect) with the extensions, it drops
very
quickly away from the inside surface of the mixing chamber and/or is pushed
or deflected away from that inside surface by other, more energetic process
component particles;
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5. the instant cooling contact and mixing of step 2 above is repeated for
the sliding, friction-heated particle disengaging from contact with the mixing
chamber surface; and
6. violent and extreme turbulence of the process component particles is
essentially instantaneous and essentially continuous (but not constant where
there is a motor shaft speed change) from the moment the thermokinetic
mixer is turned on until it is turned off at the end of the thermokinetic
heating-
mixing step, such that temperature of the entire batch is essentially uniform
through the ,mixing chamber where the temperature is measured at distances
1-2 centimeters away from friction heating surfaces of the extensions and the
inside surface of the mixing chamber.
Before the thermokinetic mixer was used to heat process component particles to
such a high temperature that they would melt together, the thermokinetic mixer
was
used primarily for mixing, with the heat generation being an unwanted side
effect to
be reduced by use of a cooling jacket outside the mixing chamber. The present
inventor has been part of the isolated effort to find uses for thermokinetic
compounding in pharmaceutical processing, with the present disclosure directed
to
the field of not only chemical composition-sparing mixing but also to cause a
structural change in heat labile pharmaceutical components.
The present disclosure is directed to at least one active pharmaceutical
ingredient "API"), preferably at least in partly crystalline form, combined
with at least
one excipient, polymeric carrier or similar less active or inactive
ingredient, hereafter
referred to as the component combination. The present disclosure provides a
method of thermokinetic mixing of the component combination in a single batch
for
only a relatively few seconds with improved devices and/or methods for
reducing
batch processing times as compared with thermokinetic mixing using only a
batch
temperature measurement to determine when thermokinetic mixing should be
terminated and the batch removed from the mixing chamber.
In a first embodiment of the present disclosure, a first, lower shaft speed
mixing
of the component combination takes place, where monitoring of the batch by
temperature rate increase determination results in a determination that a
substantial
portion of desired thermokinetic mixing has occurred, whereafter a second,
higher
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shaft speed is used to complete the desired thermokinetic mixing of the
component
combination.
In a second embodiment of the invention, a first, lower shaft speed mixing of
the
component combination takes place, where monitoring of the batch by absolute
values of batch crystallinity are determined or rates of decrease of batch
crystallinity
are determined. At a pre-determined value of crystallinity or rate of decrease
of
crystallinity, either thermokinetic mixing is terminated or a second, higher
shaft
speed is used to complete the desired thermokinetic mixing of the component
combination at a second pre-determined value of crystallinity or rate of
decrease of
crystallinity.
The discovery inherent in these two embodiments is that, after extensive trial
and
error in thermokinetic mixing of component combinations, extended exposure to
elevated temperatures required to achieve desired mixing has resulted in
degradation of expensive and heat-labile pharmaceutical drug molecules. Ways
had
to be found to reduce required mixing times. These two embodiments meet those
requirements.
The first embodiment is a result of the discovery that a first, lower shaft
speed
mixing of the component combination provides a substantial part of the desired
mixing of the component combination within just a few seconds of the start of
the
process, but that extended mixing times resulting in pharmaceutical
degradation
were apparently needed, even where a second, higher shaft speed was used later
on in the process. The first embodiment incorporates the discovery that the
first,
lower shaft speed step need only be relatively short and its end (and the
start of the
second, higher shaft speed) is triggered by a relatively substantial decline
in the rate
of temperature increase of the batch. When the temperate increase rate is
about
from 10 percent to 100 percent less than a calculated maximum rate of
temperature
increase of the batch temperature in the first few seconds or has a rate of
increase
(temperature (degrees F or C) / time (sec.)) of from 1.5 to 0 degrees /
second, the
second, higher shaft speed shall start. Surprisingly, a desired level of
mixing
(determined by trial and error, i.e., testing mixed component combinations
after
mixing) is achieved in a shorter time and generally at a lower ultimate batch
temperature with the first embodiment than using a single shaft speed for the
entire
mixing process or using only temperature measurement alone for the batch. The
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shorter processing time and lower ultimate temperature of the first embodiment
results in essentially no degradation of the pharmaceutical and, perhaps of
almost
equal value to the final product, initial crystallinity of the pharmaceutical
or drug
component is essentially eliminated. The reason for reducing crystallinity and
increasing amorphosity of the mixed component combination is now discussed.
A desired structural change in the mixed pharmaceutical components is
generally
referred to as amorphosity or an amorphous state. It is well known that the
sophisticated processes producing solid particle pharmaceuticals before final
mixing
or processing almost all result in crystalline compounds. These pure compounds
are
preferably rendered amorphous before mixing with other components to produce a
final, desired drug composition. It is well known that amorphous
pharmaceuticals
have dramatically increased predicted solubility as compared to their
crystalline
phases (Hancock et al.; What is the true solubility advantage for amorphous
pharmaceuticals?; Pharm Res. 2000 Apr;17(4):397-404);
www.ncbi.nlm.nih.gov/pubmed/10870982). The increased solubility is only one of
the
bio-availability advantages of bringing pharmaceutical compounds to an
amorphous
state before administration ¨ "The importance of amorphous pharmaceutical
solids
lies in their useful properties, common occurrence, and physicochemical
instability
relative to corresponding crystals." (Yu, L.; Amorphous pharmaceutical solids:
preparation, characterization and stabilization.; Adv Drug Deliv Rev. 2001 May
16;48(1):27-42; www.ncbi.nlm.nih.gov/pubmed/11325475). Yu further explains the
state of the art in rendering crystalline, heal labile pharmaceutical
compounds (such
as proteins and peptides) to an effective amorphous state - melt quenching,
freeze-
and spray-drying, milling, wet granulation, and drying of solvated crystals.
These
processes are time and labor intensive, must be accomplished separately from
other
components to be mixed with the final amorphous pharmaceutical solids, and
exposes the processed crystalline pharmaceutical solids to degradation and re-
crystallization. There is a need for a process which can accomplish mixing of
a
single or multiple crystalline pharmaceutical solids to produce a desired
final drug
dosage composition and at the same time achieve the desired amorphous state
desired for the pharmaceutical solids as a part of that desired final drug
dosage
composition.
The second embodiment incorporates an entirely novel method of monitoring
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thermokinetic mixing of component combinations. The present inventor has
discovered a method by which crystallinity of the mixing batch in the
thermokinetic
mixer can be measured. The atmosphere within the mixing chamber during
thermokinetic mixing is at best murky, turbulent and lasts less than about 30
.. seconds. While it would be desirable to be able to directly measure
crystallinity of
the mixing batch so that mixing could be terminated when crystallinity is
sufficiently
reduced or effectively eliminated, the method by which that might be
accomplished
has been unknown in the art of turbulent batch mixing of dry particles before
now.
The present inventor first found that Raman spectroscopy is used to measure
crystallinity of the mixed a static amount of solid materials, in this case
the
crystallinity of the mixed component combination. Commercial Raman
spectroscopes, in analyzing a static sample of the un-mixed and mixed
component
combination, allow the user to filter out all of the detected wavelengths
associated
with other components of the component combination and to detect and measure
percent crystallinity of the pharmaceutical or drug of the component
combination.
The present inventor has discovered a Raman spectroscopic probe comprising a
narrow tube with requisite lenses oriented axially within the tube, whose ends
are
open for receiving and transmitting light waves appropriate for detection by a
Raman
spectroscope. Without intending limitation thereby, appropriate Raman
spectroscopes by example for the second embodiment may be those of Princeton
Instruments, specifically the TriVista CRS
(http://www.princetoninstruments.com/products/specsys/trivistacrs/), whose
lasers
and detection apparatus are already adapted for use in such a narrow tube (in
the
case of the TriVista CRS, the tube is a standard microscope lens tube). The
second
embodiment probe uses a lens-extended tube of a Raman spectroscope so that its
distal end is directed into the mixing chamber, preferably directed so that it
can
detect crystallinity of particles in motion between rotating shaft extensions.
The
proximal end of the Raman spectroscope probe is connected with a Raman
spectroscope and device microprocessor, whose device user interface allows for
viewing and/or transmittal of Raman spectroscope crystallinity determination
data to
a mixer control microprocessor. Where the Raman spectroscope determines mixing
batch crystallinity and transmits that data to a mixer control microprocessor,
the
mixer control microprocessor can act to either terminate mixing of a component
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=
combination batch or to increase the shaft speed and thereafter terminate
mixing. In
the second embodiment, as the pharmaceutical or drug is transformed from
crystalline amorphous form, Raman scattering from pharmaceutical or drug
crystals
stops or cannot be detected, i.e., energy is now absorbed from different
energy
states than that of the pharmaceutical or drug crystals. The Raman probe
detects
when pharmaceutical or drug crystals essentially disappear, so that
temperature
measurement is not needed for process control of the thermokinetic mixing of
the
component combination.
Previous Summary of the Invention
In contrast, processing of heat labile and pharmaceutical components to mix
with other components or to be processed by themselves into a powder form
never
intends that the components reach a temperature at which they will melt.
Instead,
the desired outcome is essentially complete mixing or a powder form. If
essentially
complete amorphosity could be achieved in the same mixing step, it would avoid
a
separate processing step. The present inventor contemplated that the
thermokinetic
mixer might avoid decomposition of heat labile and pharmaceutical components
in
required mixing processing because of his years of experience in processing
commercial polymers with the thermokinetic mixer. However, he also
contemplated
that exposure to heat, even though very short in time, might result in
decomposition
of the components that typically required several previous processing steps of
special technical application at high cost. The present inventor contemplated
how it
might be possible to further reduce processing time for the mixed batches in
the
thermokinetic mixer yet still achieve essentially complete amorphosity for the
batch.
Additional Summary of the Invention for the First and Second Embodiments
In proceeding to experiment with test batches of heat labile and
pharmaceutical components in the thermokinetic mixer, the present inventor
observed a phenomenon in his years of working with thermokinetic mixers. After
an
initial mixing period at a lower shaft rotation speed, temperature of the
batch would
rise and plateau. Further processing at that lower speed would fail to produce
essentially complete amorphosity in the processed batch. The present inventor
found that increasing the shaft rotation speed to a higher level for a fairly
short
period of time produced essentially complete amorphosity in the resulting
batch, with
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substantially little decomposition of the components from exposure to the
process
heats.
However, the present inventor has found the above method of obtaining
desired results might unnecessarily extend processing time. In the present
invention,
the processing time and exposure to elevated temperatures of the processed
batch
is reduced as compared with waiting to observe a temperature plateau at a
lower
shaft rotation speed and thereafter increasing to a higher shaft rotation
speed. In the
present invention, a high speed temperature sensor accurately and essentially
instantly measures the average batch temperature, which sensed temperatures
are
stored in a mixer or batch microprocessor (comprising a CPU, a memory, a
clock,
and an input/output unit) which operates under a batch control program. Sensed
temperatures are instantly compared with one or more previously stored
temperatures and their recording times, from which data are calculated a rate
to
temperature change. Upon detection that the rate of temperature change has
reduced or increased to a desired trigger rate of temperature increase, the
shaft
rotation speed is increased from a lower shaft rotation speed to a higher
shaft
rotation speed.
The Raman spectroscopy probe is preferably located so as to detect
crystallinity of a small sample space of in-motion particles near a distal end
of the
probe, which is illuminated with a laser beam. Light from the illuminated area
is
collected with a lens and sent through a monochromator of the Raman
spectroscope. Wavelengths close to the laser and drugs or pharmaceuticals due
to
elastic Rayleigh scattering are filtered out while the rest of the collected
light is
dispersed onto a detector. The laser light interacting with molecular
vibrations,
phonons or other excitations in the system, results in the energy of the laser
photons
being shifted up or down. The shift in energy gives information about the
vibrational
modes in the system. In the case of the second embodiment, those vibrational
modes are processed by algorithm of a manufacturer of the temperature sensor
to
determine an average crystallinity of the mixing batch. Because detection time
of
mixing batch crystallinity may be extended up to about 3 seconds, the device
microprocessor or the mixer control microprocessor optionally operate a
crystallinity
setpoint program which determines rates of decline in batch crystallinity and
are
stored for predictive use. Because 3 seconds or more (for batch crystallinity
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detection by Raman probe) of over-mixing may result in drug or pharmaceutical
degradation, test batches of a desired component combination are preferably
tested
to obtain termination of mixing or speed increase triggering setpoints. These
triggering setpoints be used with a currently measured absolute value of
crystallinity
or rate of decline in crystallinity so that mixing will be stopped (or shaft
speed
increased) to obtain the desired thermokinetic mixing before the desired
crystallinity
level is currently detected.
Referring now to the first embodiment, the present inventor has also
discovered a rate of temperature change at a point on the first temperature
plateau
that corresponds to the change in viscosity indicating the optimal time at
which to
increase the shaft rotation speed. The present invention measures rate of
temperature change of the mixing batch and increases shaft rotation speed from
a
lower to a higher level when (1) the rate of change of the average batch
temperature
is calculated to have reached a trigger rate of temperature change indicating
the
batch has achieved a required change in viscosity indicating a significant
increase in
amorphosity or (2) the rate of change of the average batch temperature is
calculated
to have reached an anticipatory trigger rate of temperature change which
indicates
that, after taking into account processing speed of temperature detection and
calculations, the batch will achieve a required change in viscosity indicating
a
significant increase in amorphosity in a short process period. In the case of
process
method (2), shaft rotation speed is increased to a higher level before the
desired
rate of temperature change is actually detected and calculated to avoid
unnecessary
mixing time after detection and calculation of that desired rate of
temperature
change.
In the present invention, resulting pharmaceutical compositions preferably
have increased bioavailability and stability due to essentially complete
mixing and
amorphosity.
As described above, a thermokinetic mixer provides blending and dispersing
of an autoheated mixture in the mixing chamber of a high speed mixer, where a
first
speed is changed mid-processing to a second speed upon achieving a first
desired
process parameter. In another embodiment, the second speed may be maintained
until a final process parameter is achieved, whereupon shaft rotation is
stopped and
a melt blended batch is withdrawn or ejected from the mixing chamber for
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CA 2979451 2017-09-15
processing. In another embodiment, one or more intermediate speed changes may
be made to the shaft rotational speed between the second speed and stopping
the
shaft rotation. Process parameters which determine shaft speed changes are
predetermined and may be sensed and displayed, calculated, inferred, or
otherwise
.. established with reasonable certainty so that the speed change(s) are made
during a
single, rotationally continuous processing of a batch in a mixing chamber of
the high
speed mixer. Another embodiment is the use of variations in the shape, width
and
angle of the facial portions of the shaft extensions or projections that
intrude into the
main processing volume to control translation of rotational shaft energy
delivered to
the extensions or projections into heating energy within particles impacting
the
portions of the extensions or projections.
The present inventor investigated the melt blending of various mixtures
including thermolabile components in a thermokinetic mixing chamber. The
present
inventor unexpectedly found that using multiple speeds during a single,
rotationally
continuous operation on certain batches containing thermolabile components
solved
the problem of exceeding a limit temperature or excessive heat input for the
batch.
The present inventor also surprisingly found that varying the shape, width and
angle
away from a shaft axis plane of a shaft extension or projection provided a
method of
controlling the shear delivered to a particle, which in turn provided control
over shaft
energy translated into heat energy available for softening or melting a
polymer part
of a particle in a thermokinetic mixing chamber.
An embodiment of the present disclosure is a method of blending a
composition of two or more ingredients, wherein the ingredients comprise one
or
more heat sensitive or thermolabile components, wherein the resulting
composition
is amorphous, homogenous, heterogenous, or heterogeneously homogenous, the
method comprising mixing the ingredients in a thermokinetic mixing chamber,
wherein a thermokinetic mixer shaft is operated at a first speed until
achieving a
predetermined parameter, at which time the shaft speed is adjusted to a second
speed for a second time period, wherein the mixing process is substantially
.. uninterrupted between the first and second time periods. In another
embodiment of
the present disclosure, the thermokinetic mixer shaft is operated at one or
more
speeds until achieving a predetermined parameter, at which time the shaft
speed is
adjusted to a different speed for a different time period, wherein the mixing
process
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is substantially uninterrupted between the two or more time periods. An
example of
such an embodiment is a method of blending a composition of two or more
ingredients, wherein a thermokinetic mixer shaft is operated at a first speed
until
achieving a predetermined parameter, at which time the shaft speed is adjusted
to a
second speed for a second time period, wherein the mixing process is
substantially
uninterrupted between the first and second time periods, and wherein at the
end of
the second time period a rotational speed of the shaft is changed from the
second
speed to a third speed for a third time period upon achieving a predetermined
parameter. In one embodiment, the mixing process is substantially
uninterrupted
between the second and third time periods.
In certain embodiments, the heat sensitive or thermolabile components may
comprise one or more active pharmaceutical ingredients, one or more
pharmaceutically acceptable excipients, or one or more pharmaceutically
acceptable
heat sensitive polymers. In other embodiments, the heat sensitive or
thermolabile
components may comprise one or more active pharmaceutical ingredients and one
or more pharmaceutically acceptable excipients or heat sensitive polymers. In
other
embodiments, the active pharmaceutical ingredients and one or more
pharmaceutically acceptable excipients are added in a ratio of from about 1:2
to 1:9,
respectively. In still other embodiments, the active pharmaceutical
ingredients and
one or more pharmaceutically acceptable heat sensitive polymers are added in a
ratio of from about 1:2 to 1:9, respectively. In certain embodiments, the
second time
period may be at least about five percent, 10 percent, 15 percent, 20 percent,
25
percent or more of the first time period. In other embodiments, the speed
during the
second time period is increased by about 100 revolutions per minute ("RPM"),
200
RPM, 300 RPM, 400 RPM, 500 RPM, 600 RPM, 700 RPM, 800 RPM, 900 RPM,
1000 RPM, 1100 RPM, 1200 RPM, 1300 RPM, 1400 RPM, 1500 RPM, 1600 RPM,
1700 RPM, 1800 RPM, 1900 RPM, 2000 RPM, 2100 RPM, 2200 RPM, 2300 RPM,
2400 RPM, 2500 RPM, or more as compared to the speed during the first time
period. For example, in one embodiment the first speed is greater than 1000
RPM
and the second speed is 200 to 400 RPM greater than the first speed. In
another
embodiment, the first speed is greater than 1000 RPM and the second speed is
200
to 1000 RPM greater than the first speed. In still another embodiment, the
first
speed is greater than 1000 RPM and the second speed is 200 to 2500 RPM greater
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than the first speed.
In one embodiment, the end of the first time period is substantially before
the
mixing chamber temperature reaches the shear transition temperature or melting
point of any substantial component of the ingredients. In another embodiment,
the
end of the first time period is a predetermined time period and a change to
the
second speed is made automatically by the thermokinetic mixer at the end of
the
first time period. In yet another embodiment, the end of the first time period
is
substantially before the mixing chamber temperature reaches the shear
transition
temperature of an active pharmaceutical ingredient in the ingredients. In
still
another embodiment, the end of the first time period is substantially before
mixing
chamber temperature reaches the shear transition temperature of an excipient
in the
ingredients. In another embodiment, the end of the first time period is
substantially
before mixing chamber temperature reaches the shear transition temperature of
a
heat sensitive polymer in the ingredients.
In one embodiment, the end of the second or any subsequent time period is
substantially before an active pharmaceutical ingredient experiences
substantial
thermal degradation. In another embodiment, the end of the second or any
subsequent time period is substantially before an excipient ingredient
experiences
substantial thermal degradation. In yet another embodiment, the end of the
second
or any subsequent time period is substantially before a heat sensitive polymer
ingredient experiences substantial thermal degradation. In one embodiment, at
the
end of the second or any subsequent time period the active pharmaceutical
ingredient and an excipient of the ingredients are substantially amorphous. In
another embodiment, at the end of the second or any subsequent time period the
active pharmaceutical ingredient and a heat sensitive polymer of the
ingredients are
substantially amorphous. In other embodiments, upon achieving a final process
parameter, the shaft rotation is stopped and a batch or composite is withdrawn
or
ejected from the mixing chamber for further processing. In certain
embodiments, the
batch or composite is withdrawn or ejected at or below the glass transition
temperature of at least one of the components of the batch or composite. In
other
embodiments, the batch or composite is further processed by hot melt
extrusion,
melt granulation, compression molding, tablet compression, capsule filling,
film-
coating, or injection molding. In other embodiments, the batch or composite is
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withdrawn or ejected at the beginning of a RPM plateau, for example before
degradation occurs in the batch or composite. In other embodiments, the RPM
deceleration prior to withdrawal or ejection of the batch or composite is
modulated to
produce a more uniform batch or composite.
Another embodiment of the present disclosure is directed to a method of
compounding one or more active pharmaceutical ingredients and at least one
polymeric pharmaceutically acceptable excipient to produce an amorphous,
homogenous, heterogenous, or heterogeneously homogenous composition, the
method comprising thermokinetic mixing of the active pharmaceutical
ingredient(s)
.. and at least one polymeric pharmaceutically acceptable excipient in a
chamber at a
first speed effective to increase the temperature of the mixture, and at a
time point at
which the temperature is below the shear transition temperature of any active
pharmaceutical ingredient or polymeric pharmaceutically acceptable excipient
in the
mixture, increasing the mixer rotation to a second speed to produce an
amorphous,
homogenous, heterogenous, or heterogeneously homogenous composition, wherein
the increase is accomplished without stopping the mixing or opening the
chamber.
In another embodiment of the present disclosure, the method comprises
thermokinetic mixing in a chamber at one or more speeds effective to increase
the
temperature of the mixture, at which time the shaft speed is adjusted to a
different
speed for a different time period, and at a time point at which the
temperature is
below the shear transition temperature of any active pharmaceutical ingredient
or
polymeric pharmaceutically acceptable excipient in the mixture, and increasing
the
mixer rotation to one or more different speeds, wherein the increase is
accomplished
without stopping the mixing or opening the chamber.
Certain embodiments of the present disclosure are directed to thermokinetic
mixers used to produce a pharmaceutical composition comprising one or more
heat
sensitive or thermolabile components. Various embodiments of the mixer may
comprise one or more and any combination of the following: (1) a mixing
chamber,
for example a substantially cylindrical mixing chamber; (2) a shaft disposed
through
the center axis of the mixing chamber; (3) an electric motor connected to the
shaft,
for example which is effective to impart rotational motion to the shaft; (4)
one or
more projections or extensions from the shaft and perpendicular to the long
axis of
the shaft; (5) one more heat sensors, for example attached to a wall of the
mixing
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chamber and operative to detect heat or temperature of at least a portion of
the
interior of the mixing chamber; (6) a variable frequency device, for example
connected to the motor; (7) a door disposed in a wall of the mixing chamber,
for
example which is effective when opened during a process run to allow the
contents
.. of the mixing chamber to pass out of the mixing chamber; and (8) an
electronic
controller. In certain embodiments, a hygroscopic condition is maintained
within the
thermokinetic mixer. In other embodiments, the thermokinetic mixers are
designed
to maximize shear during batch processing.
In certain embodiments, the electronic controller is in communication with the
temperature sensors, the door and the variable frequency device. In some
embodiments, the electronic controller comprises a user input device, a timer,
an
electronic memory device configured to accept user input of process parameters
or
predetermined parameters for two or more stages of a thermokinetic mixing
processing, and a display. In an embodiment, the process parameters or
predetermined parameters are saved in the memory device and displayed on the
monitor for one or more stages of a process run. In certain embodiments, when
one
of the predetermined parameters is met during a stage of a processing run, the
electronic controller automatically moves the process run to the subsequent
stage.
In other embodiments, the mixing chamber is interiorly lined by interior liner
pieces.
The liner pieces may be made of material that minimizes any stickiness of the
batch
during processing, for example stainless steel and other such steel alloys,
titanium
alloys (such as nitrided or nitride-containing titanium), and wear and heat
resistant
polymers (such as Teflon ).
In one embodiment of the present disclosure, at least one of the temperature
sensors detects infrared radiation, for example wherein the radiation level is
output
as temperature on the display. In other embodiments, the predetermined
parameters may be any one or a combination of the following: temperature, rate
of
temperature change, shaft rotational speed (e.g., rate of acceleration and
deceleration), amperage draw of the electric motor, time of stage, or rate of
withdrawal or exit of the batch or composite. One of skill in the art will be
able to
change each of the following parameters to obtain a batch or composite with
the
desired characteristics through routine experimentation. In another
embodiment, the
output display may be any one or a combination of the following: chamber
CA 2979451 2017-09-15
temperature, motor revolutions per minute, amperage draw of the motor, or
cycle
elapsed time.
In certain embodiments of the present disclosure, the one or more projections
or extensions from the shaft comprise a base and an end portion, and, for
example,
the end portion may be removable from the base portion and the base portion
may
be removable from the shaft. In other embodiments, the projections or
extensions
are replaceable in the thermokinetic mixer, for example based on wear and tear
or
different batch parameters. In one embodiment, the one or more projections or
extensions from the shaft comprise one or more main facial portions having a
width
of at least about 0.75 inches, at an angle of between 15 to 80 degrees from a
shaft
axis plane. In other embodiments, the one or more projections or extensions
from
the shaft comprise one or more main facial portions having a width of at least
about
0.80 inches, 0.85 inches, 0.90 inches, 0.95 inches, 1.0 inches, 1.1 inches,
1.2
inches, 1.3 inches, 1.4 inches, 1.5 inches, 1.6 inches, 1.7 inches, 1.8
inches, 1.9
inches, 2.0 inches, 2.1 inches, 2.2 inches, 2.3 inches, 2.4 inches, 2.5
inches, 2.6
inches, 2.7 inches, 2.8 inches, 2.9 inches, 3.0 inches, 3.1 inches, 3.2
inches, 3.3
inches, 3.4 inches, 3.5 inches, 3.6 inches, 3.7 inches, 3.8 inches, 3.9
inches, 4.0
inches, 4.1 inches, 4.2 inches, 4.3 inches, 4.4 inches, 4.5 inches, 4.6
inches, 4.7
inches, 4.8 inches, 4.9 inches, 5.0 inches, or greater, at an angle of about
15, 20,
25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 degrees from a shaft axis
plane. In
certain embodiment, the one or more projections or extensions from the shaft
control
translation of rotational shaft energy delivered to the projections or
extensions into
heating energy within particles impacting the projections.
In other embodiments, these dimensions of the one or more projections or
extensions from the shaft are designed to increase the shear profile of the
population of shear-resistant particles in the batch, for example to produce
substantially amorphous composites. In certain embodiments, the dimensions of
the
one or more projections or extensions from the shaft are designed to produce
composites that are at least about 60, 65, 70, 75, 80, 85, 90, 95, or 99
percent
amorphous.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
The following drawings form part of the present specification and are included
16
CA 2979451 2017-09-15
to further demonstrate certain aspects of the present disclosure. The
disclosure
may be better understood by reference to one or more of these drawings in
combination with the detailed description of specific embodiments presented
herein.
FIG. 1. A view of the thermokinetic mixer assembly.
FIG. 2. An exploded view of the thermokinetic mixer.
FIG. 3. A shaft-radial cutaway view of a thermokinetic mixing chamber.
FIG. 4. An exploded view of the thermokinetic mixing chamber.
FIG. 5. Analysis of batch sensed temperature, shaft rotational speeding in
RPMs, and amperage draw on the motor as a directly proportional measure of
energy input into the batch at any moment with one rotational shaft speed.
FIG. 6. Analysis of batch sensed temperature, shaft rotational speeding in
RPMs, and amperage draw on the motor as a directly proportional measure of
energy input into the batch at any moment with two rotational shaft speeds.
FIG. 7. A graph block diagram of a thermokinetic mixer process at two or
more rotational shaft speeds.
FIG. 8. A cross section of a main facial portion of a prior art shaft
extension.
FIG. 9. A cross section of a main facial portion of a shaft extension with a
shaft axial plane at an angle of about 15 degrees.
FIG. 10. A cross section of a main facial portion of a shaft extension with a
shaft axial plane at an angle of about 30 degrees.
FIG. 11. A cross section of a main facial portion of a shaft extension with a
shaft axial plane at an angle of about 45 degrees.
FIG. 12. A cross section of a main facial portion of a shaft extension with a
shaft axial plane at an angle of about 60 degrees.
FIG. 13. An alternative design of a cross section of a main facial portion of
a
shaft extension.
FIG. 14. An alternative design of a cross section of a main facial portion of
a
shaft extension.
17
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FIG. 15. An alternative design of a cross section of a main facial portion of
a
shaft extension.
FIG. 16. An alternative design of a cross section of a main facial portion of
a
shaft extension.
FIG. 17. An alternative design of a cross section of a main facial portion of
a
shaft extension.
FIG. 18. An alternative design of a cross section of a main facial portion of
a
shaft extension.
FIG. 19. An exploded view of the thermokinetic mixer showing internal liner
pieces.
FIG. 20. A generalized side view of a shaft extension's top face interaction
with an inside surface of a mixing chamber.
FIG. 21. A perspective view of a shaft extension with variable top face path
lengths.
FIG. 22. An alternative design of a front face of a shaft extension.
FIG. 23 A flow diagram describing the alternate embodiment of the invention.
FIG. 24 A high level process flow diagram of the alternate embodiment of the
invention using a trigger setpoint to increase shaft rotation rate and/or to
stop
thermokinetic mixing.
FIG. 25 Analysis graph of a single shaft speed batch showing sensed
temperature in degrees F and shaft rotational speeding in RPMs against process
time, where the process is stopped at a detected temperature plateau.
FIG. 26 Analysis graph of a single shaft speed batch showing sensed
temperature in degrees F and shaft rotational speeding in RPMs against process
time, where the process is stopped after a detected temperature plateau at a
second
period time, or a detected reduction in crystallinity.
FIG. 27 Analysis graph of a two shaft speed batch showing sensed
temperature in degrees F and shaft rotational speeding in RPMs against process
time, where the shaft speed is increased at a detected temperature plateau and
the
process is stopped at detected temperature, second speed time, or a detected
18
CA 2979451 2017-09-15
reduction in crystallinity.
DETAILED DESCRIPTION OF THE INVENTION
Although making and using various embodiments of the present disclosure
are discussed in detail below, it should be appreciated that the present
disclosure
provides many inventive concepts that may be embodied in a wide variety of
contexts. The specific aspects and embodiments discussed herein are merely
illustrative of ways to make and use the disclosure, and do not limit the
scope of the
disclosure.
To facilitate the understanding of this disclosure, a number of terms are
defined below. Terms defined herein have meanings as commonly understood by a
person of ordinary skill in the areas relevant to the present disclosure.
Terms such
as "a", "an" and "the" are not intended to refer to only a singular entity,
but include
the general class of which a specific example may be used for illustration.
With
regard to the values or ranges recited herein, the term "about" is intended to
to
capture variations above and below the stated number that may achieve
substantially the same results as the stated number. In the present
disclosure, each
of the variously stated ranges is intended to be continuous so as to include
each
numerical parameter between the stated minimum and maximum value of each
range. For Example, a range of about 1 to about 4 includes about 1, 1, about
2, 2,
about 3, 3, about 4, and 4. The terminology herein is used to describe
specific
embodiments of the disclosure, but their usage does not delimit the
disclosure,
except as outlined in the claims.
As used herein, the term "thermokinetic compounding" or "TKC" refers to a
method of thermokinetic mixing until melt blended. TKC may also be described
as a
thermokinetic mixing process in which processing ends at a point sometime
prior to
agglomeration.
As used herein, the term "main facial portion" refers to the "top face" of a
shaft extension. The top face of a shaft extension is the face facing the
inside wall
of the mixing chamber of a thermokinetic mixer.
As used herein, the term "shear transition temperature" refers to the point at
19
CA 2979451 2017-09-15
which further energy input does not result in an immediate rise in
temperature.
As used herein, the phrase "a homogenous, heterogenous, or
heterogeneously homogenous composite or an amorphous composite" refers to the
various compositions that can be made using the TKC method.
As used herein, the term "heterogeneously homogeneous composition" refers
to a material composition having at least two different materials that are
evenly and
uniformly distributed throughout the volume.
As used herein, "bioavailability" is a term meaning the degree to which a drug
becomes available to the target tissue after being administered to the body.
Poor
bioavailability is a significant problem encountered in the development of
pharmaceutical compositions, particularly those containing an active
ingredient that
is not highly soluble. In certain embodiments such as formulations of
proteins, the
proteins may be water soluble, poorly soluble, not highly soluble, or not
soluble. The
skilled artisan will recognize that various methodologies may be used to
increase the
solubility of proteins, e.g., use of different solvents, excipients, carriers,
formation of
fusion proteins, targeted manipulation of the amino acid sequence,
glycosylation,
lipidation, degradation, combination with one or more salts and the addition
of
various salts.
As used herein, the phrase "pharmaceutically acceptable" refers to molecular
entities, compositions, materials, excipients, carriers, and the like that do
not
produce an allergic or similar untoward reaction when administered to humans
in
general.
As used herein, the term "active pharmaceutical ingredient" or "API" is
interchangeable with the terms "drug," "drug product," "medication," "liquid,"
"biologic," or "active ingredient." As used herein, an "API" is any component
intended to furnish pharmacological activity or other direct effect in the
diagnosis,
cure, mitigation, treatment, or prevention of disease, or to affect the
structure or any
function of the body of humans or other animals. In certain embodiments, the
aqueous solubility of the API may be poorly soluble.
Examples of APIs that may be utilized in the present disclosure include, but
are not limited to, antibiotics, analgesics, vaccines, anticonvulsants, anti-
diabetic
agents, anti-fungal agents, anti-neoplastic agents, anti-parkinsonian agents,
anti-
CA 2979451 2017-09-15
rheumatic agents, appetite suppressants, biological response modifiers,
cardiovascular agents, central nervous system stimulants, contraceptive
agents,
dietary supplements, vitamins, minerals, lipids, saccharides, metals, amino
acids
(and precursors), nucleic acids and precursors, contrast agents, diagnostic
agents,
dopamine receptor agonists, erectile dysfunction agents, fertility agents,
gastrointestinal agents, hormones, immunomodulators, anti-hypercalcemia
agents,
mast cell stabilizers, muscle relaxants, nutritional agents, ophthalmic
agents,
osteoporosis agents, psychotherapeutic agents, parasympathomimetic agents,
parasympatholytic agents, respiratory agents, sedative hypnotic agents, skin
and
mucous membrane agents, smoking cessation agents, steroids, sympatholytic
agents, urinary tract agents, uterine relaxants, vaginal agents, vasodilator,
anti-
hypertensive, hyperthyroids, anti-hyperthyroids, anti-asthmatics and vertigo
agents.
In certain embodiments, the API is a poorly water-soluble drug or a drug with
a high
melting point.
The API may be found in the form of one or more pharmaceutically
acceptable salts, esters, derivatives, analogs, prodrugs, and solvates
thereof. As
used herein, a "pharmaceutically acceptable salt" is understood to mean a
compound formed by the interaction of an acid and a base, the hydrogen atoms
of
the acid being replaced by the positive ion of the base. Non-limiting examples
of
pharmaceutically acceptable salts include sulfate, citrate, acetate, oxalate,
chloride,
bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate,
lactate,
salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate,
ascorbate,
succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate,
formate, benzoate, glutamate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate, and pamoate. Another method for defining
the ionic salts may be as an acidic functional group, such as a carboxylic
acid
functional group, and a pharmaceutically acceptable inorganic or organic base.
Non-limiting examples of bases include, but are not limited to, hydroxides of
alkali
metals such as sodium, potassium and lithium; hydroxides of calcium and
magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia; and
organic amines, such as unsubstituted or hydroxy substituted mono-, di-, or
trialkylamines; dicyclohexylamine; tributylamine; pyridine; N-methyl-N-
ethylamine;
diethylamine; triethylamine; mono-, bis- or tris-(2-hydroxy-lower alkyl
amines), such
21
CA 2979451 2017-09-15
=
as mono- bis- or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or
tris-
(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxy lower alkyl)-amines,
such as N,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine; N-
methyl-D-glucamine; and amino acids such as arginine, lysine, and the like.
A variety of administration routes are available for delivering the APIs to a
patient in need. The particular route selected will depend upon the particular
drug
selected, the weight and age of the patient, and the dosage required for
therapeutic
effect. The pharmaceutical compositions may conveniently be presented in unit
dosage form. The APIs suitable for use in accordance with the present
disclosure,
and their pharmaceutically acceptable salts, derivatives, analogs, prodrugs,
and
solvates thereof, can be administered alone, but will generally be
administered in
admixture with a suitable pharmaceutical excipient, diluent, or carrier
selected with
regard to the intended route of administration and standard pharmaceutical
practice.
The APIs may be used in a variety of application modalities, including oral
delivery as tablets, capsules or suspensions; pulmonary and nasal delivery;
topical
delivery as emulsions, ointments or creams; transdermal delivery; and
parenteral
delivery as suspensions, microemulsions or depot. As used herein, the term
"parenteral" includes subcutaneous, intravenous, intramuscular, or infusion
routes of
administration.
The excipients and adjuvants that may be used in the presently disclosed
compositions and composites, while potentially having some activity in their
own
right, for example, antioxidants, are generally defined for this application
as
compounds that enhance the efficiency and/or efficacy of the active
ingredients. It is
also possible to have more than one active ingredient in a given solution, so
that the
particles formed contain more than one active ingredient.
As stated, excipients and adjuvants may be used to enhance the efficacy and
efficiency of the APIs. Non-limiting examples of compounds that can be
included
are binders, cryoprotectants, lyoprotectants, surfactants, fillers,
stabilizers, polymers,
protease inhibitors, antioxidants and absorption enhancers. The excipients may
be
chosen to modify the intended function of the active ingredient by improving
flow, or
bio-availability, or to control or delay the release of the API. Specific
nonlimiting
examples include: sucrose, trehaolose, Span 80, Tween 80, Brij 35, Brij 98,
Pluronic,
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CA 2979451 2017-09-15
sucroester 7, sucroester 11, sucroester 15, sodium lauryl sulfate, oleic acid,
laureth-
9, laureth-8, lauric acid, vitamin E TPGS, Gelucire 50/13, Gelucire 53/10,
Labrafil,
dipalmitoyl phosphadityl choline, glycolic acid and salts, deoxycholic acid
and salts,
sodium fusidate, cyclodextrins, polyethylene glycols, labrasol, polyvinyl
alcohols,
polyvinyl pyrrolidones and tyloxapol. Using the process of the present
disclosure,
the morphology of the active ingredients can be modified, resulting in highly
porous
microparticles and nanoparticles.
Exemplary thermal binders that may be used in the presently disclosed
compositions and composites include but are not limited to polyethylene oxide;
polypropylene oxide; polyvinylpyrrolidone; polyvinylpyrrolidone-co-
vinylacetate;
acrylate and methacrylate copolymers; polyethylene; polycaprolactone;
polyethylene-co-polypropylene; alkylcelluloses such as methylcellulose;
hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose, and hydroxybutylcellulose; hydroxyalkyl
alkylcelluloses such
as hydroxyethyl methylcellulose and hydroxypropyl methylcellulose; starches,
pectins; polysaccharides such as tragacanth, gum arabic, guar gum, and xanthan
gum. One embodiment of the binder is poly(ethylene oxide) (PEO), which can be
purchased commercially from companies such as the Dow Chemical Company,
which markets PEO under the POLY OX.TM. trademark exemplary grades of which
can include WSR N80 having an average molecular weight of about 200,000;
1,000,000; and 2,000,000.
Suitable grades of PEO can also be characterized by viscosity of solutions
containing fixed concentrations of PEO, such as for example:
POLYOX Viscosity Range
Aqueous Solution
Water-Soluble Resin NF
at 25 C, mPa.s
POLYOX Water-Soluble Resin NF WSR N-10 30-50 (5% solution)
POLYOX Water-Soluble Resin NF WSR N-80 55-90 (5% solution)
POLYOX Water-Soluble Resin NF WSR N-
750 600-1,200 (5% solution)
POLYOX Water-Soluble Resin NF WSR-205 4,500-8,800 (5% solution)
POLYOX Water-Soluble Resin NF WSR-1105 8,800-17,600 (5% solution)
POLYOX Water-Soluble Resin NF WSR N- 400-800 (2% solution)
23
CA 2979451 2017-09-15
'
POLYOX Viscosity Range
Aqueous Solution
Water-Soluble Resin NF
at 25 C, mPa.s
12K
POLYOX Water-Soluble Resin NF WSR N-
2,000-4,000 (20 60K /0 solution)
POLYOX Water-Soluble Resin NF WSR-301 1,650-5,500 (1% solution)
POLYOX Water-Soluble Resin NF WSR
5,500-7,500(1% solution)
Coagulant
POLYOX Water-Soluble Resin NF WSR-303 7,500-10,000(1% solution)
Suitable thermal binders that may or may not require a plasticizer include,
for
example, Eudragit.TM. RS PO, Eudragit.TM. S100, Kollidon SR (poly(vinyl
acetate)-
co-poly(vinylpyrrolidone) copolymer), Ethocel.TM. (ethylcellulose), HPC
(hydroxypropylcellulose), cellulose acetate butyrate, poly(vinylpyrrolidone)
(PVP),
poly(ethylene glycol) (PEG), poly(ethylene oxide) (PEO), poly(vinyl alcohol)
(PVA),
hydroxypropyl methylcellulose (HPMC), ethylcellulose (EC),
hydroxyethylcellulose
(HEC), sodium carboxymethyl-cellulose (CMC), dimethylaminoethyl methacrylate--
methacrylic acid ester copolymer, ethylacrylate--methylmethacrylate copolymer
(GA-
MMA), C-5 or 60 SH-50 (Shin-Etsu Chemical Corp.), cellulose acetate phthalate
(CAP), cellulose acetate trimelletate (CAT), poly(vinyl acetate) phthalate
(PVAP),
hydroxypropylmethylcellulose phthalate (HPMCP), poly(methacrylate
ethylacrylate)
(1:1) copolymer (MA-EA), poly(methacrylate methylmethacrylate) (1:1) copolymer
(MA-MMA), poly(methacrylate methylmethacrylate) (1:2) copolymer, Eudragit L-30-
D.TM. (MA-EA, 1:1), Eudragit L-100-55.TM. (MA-EA, 1:1),
hydroxypropylmethylcellulose acetate succinate (HPMCAS), Coateric.TM. (PVAP),
Aquateric.TM. (CAP), and AQUACOAT.TM. (HPMCAS), polycaprolactone, starches,
pectins; polysaccharides such as tragacanth, gum arabic, guar gum, and xanthan
gum.
The stabilizing and non-solubilizing carrier may also contain various
functional
excipients, such as: hydrophilic polymer, antioxidant, super-disintegrant,
surfactant
including amphiphillic molecules, wetting agent, stabilizing agent, retardant,
similar
functional excipient, or combination thereof, and plasticizers including
citrate esters,
polyethylene glycols, PG, triacetin, diethylphthalate, castor oil, and others
known to
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CA 2979451 2017-09-15
=
those or ordinary skill in the art. Extruded material may also include an
acidifying
agent, adsorbent, alkalizing agent, buffering agent, colorant, flavorant,
sweetening
agent, diluent, opaquant, complexing agent, fragrance, preservative or a
combination thereof.
Exemplary hydrophilic polymers which can be a primary or secondary
polymeric carrier that can be included in the composites or composition
disclosed
herein include poly(vinyl alcohol) (PVA), polyethylene-polypropylene glycol
(e.g.
POLOXAMER.TM.), carbomer, polycarbophil, or chitosan. Hydrophilic polymers for
use with the present disclosure may also include one or more of hydroxypropyl
methylcellulose, carboxymethylcellulose, hydroxypropyl cellulose, hydroxyethyl
cellulose, methylcellulose, natural gums such as gum guar, gum acacia, gum
tragacanth, or gum xanthan, and povidone. Hydrophilic polymers also include
polyethylene oxide, sodium carboxymethycellulose, hydroxyethyl methyl
cellulose,
hydroxymethyl cellulose, carboxypolymethylene, polyethylene glycol, alginic
acid,
gelatin, polyvinyl alcohol, polyvinylpyrrolidones, polyacrylamides,
polymethacrylamides, polyphosphazines, polyoxazolidines,
poly(hydroxyalkylcarboxylic acids), carrageenate alginates, carbomer, ammonium
alginate, sodium alginate, or mixtures thereof.
By "immediate release" is meant a release of an active agent to an
environment over a period of seconds to no more than about 30 minutes once
release has begun and release begins within no more than about 2 minutes after
administration. An immediate release does not exhibit a significant delay in
the
release of drug.
By "rapid release" is meant a release of an active agent to an environment
over a period of 1-59 minutes or 0.1 minute to three hours once release has
begun
and release can begin within a few minutes after administration or after
expiration of
a delay period (lag time) after administration.
As used herein, the term "extended release" profile assumes the definition as
widely recognized in the art of pharmaceutical sciences. An extended release
dosage form will release the drug (i.e., the active agent or API) at a
substantially
constant rate over an extended period of time or a substantially constant
amount of
drug will be released incrementally over an extended period of time. An
extended
CA 2979451 2017-09-15
release tablet generally effects at least a two-fold reduction in dosing
frequency as
compared to the drug presented in a conventional dosage form (e.g., a solution
or
rapid releasing conventional solid dosage forms).
By "controlled release" is meant a release of an active agent to an
environment over a period of about eight hours up to about 12 hours, 16 hours,
18
hours, 20 hours, a day, or more than a day. By "sustained release" is meant an
extended release of an active agent to maintain a constant drug level in the
blood or
target tissue of a subject to which the device is administered.
The term "controlled release", as regards to drug release, includes the terms
"extended release", "prolonged release", "sustained release", or "slow
release", as
these terms are used in the pharmaceutical sciences. A controlled release can
begin within a few minutes after administration or after expiration of a delay
period
(lag time) after administration.
A slow release dosage form is one that provides a slow rate of release of drug
so that drug is released slowly and approximately continuously over a period
of 3 hr,
6 hr, 12 hr, 18 hr, a day, 2 or more days, a week, or 2 or more weeks, for
example.
The term "mixed release" as used herein refers to a pharmaceutical agent
that includes two or more release profiles for one or more active
pharmaceutical
ingredients. For example, the mixed release may include an immediate release
and
an extended release portion, each of which may be the same API or each may be
a
different API.
A timed release dosage form is one that begins to release drug after a
predetermined period of time as measured from the moment of initial exposure
to
the environment of use.
A targeted release dosage form generally refers to an oral dosage form that is
designed to deliver drug to a particular portion of the gastrointestinal tract
of a
subject. An exemplary targeted dosage form is an enteric dosage form that
delivers
a drug into the middle to lower intestinal tract but not into the stomach or
mouth of
the subject. Other targeted dosage forms can deliver to other sections of the
gastrointestinal tract such as the stomach, jejunum, ileum, duodenum, cecum,
large
intestine, small intestine, colon, or rectum.
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By "delayed release" is meant that initial release of drug occurs after
expiration of an approximate delay (or lag) period. For example, if release of
drug
from an extended release composition is delayed two hours, then release of the
drug begins at about two hours after administration of the composition, or
dosage
form, to a subject. In general, a delayed release is opposite of an immediate
release, wherein release of drug begins after no more than a few minutes after
administration. Accordingly, the drug release profile from a particular
composition
can be a delayed-extended release or a delayed-rapid release. A "delayed-
extended" release profile is one wherein extended release of drug begins after
expiration of an initial delay period. A "delayed-rapid" release profile is
one wherein
rapid release of drug begins after expiration of an initial delay period.
A pulsatile release dosage form is one that provides pulses of high active
ingredient concentration, interspersed with low concentration troughs. A
pulsatile
profile containing two peaks may be described as "bimodal." A pulsatile
profile of
more than two peaks may be described as multi-modal.
A pseudo-first order release profile is one that approximates a first order
release profile. A first order release profile characterizes the release
profile of a
dosage form that releases a constant percentage of an initial drug charge per
unit
time.
A pseudo-zero order release profile is one that approximates a zero-order
release profile. A zero-order release profile characterizes the release
profile of a
dosage form that releases a constant amount of drug per unit time.
The resulting composites or compositions disclosed herein may also be
formulated to exhibit enhanced dissolution rate of a formulated poorly water
soluble
drug.
An example of a composition or formulation having a stable release profile
follows. Two tablets having the same formulation are made. The first tablet is
stored for one day under a first set of conditions, and the second tablet is
stored for
four months under the same first set of conditions. The release profile of the
first
tablet is determined after the single day of storage and the release profile
of the
second tablet is determined after the four months of storage. If the release
profile of
the first tablet is approximately the same as the release profile of the
second tablet,
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CA 2979451 2017-09-15
then the tablet/film formulation is considered to have a stable release
profile.
Another example of a composition or formulation having a stable release
profile follows. Tablets A and B, each comprising a composition according to
the
present disclosure, are made, and Tablets C and D, each comprising a
composition
not according to the present disclosure, are made. Tablets A and C are each
stored
for one day under a first set of conditions, and tablets B and D are each
stored for
three months under the same first set of conditions. The release profile for
each of
tablets A and C is determined after the single day of storage and designated
release
profiles A and C, respectively. The release profile for each of tablet B and D
is
determined after the three months of storage and designated release profiles B
and
D, respectively. The differences between release profiles A and B are
quantified as
are the differences between release profiles C and D. If the difference
between the
release profiles A and B is less than the difference between release profiles
C and
D, tablets A and B are understood to provide a stable or more stable release
profile.
Specifically, the TKC process can be used for one or more of the following
pharmaceutical applications.
Dispersion of one or more APIs, wherein the API is a small organic molecule,
protein, peptide, or polynucleic acid; in polymeric and/or non-polymeric
pharmaceutically acceptable materials for the purpose of delivering the API to
a
patient via oral, pulmonary, parenteral, vaginal, rectal, urethral,
transdermal, or
topical routes of delivery.
Dispersion of one or more APIs, wherein the API is a small organic molecule,
protein, peptide, or polynucleic acid; in polymeric and/or non-polymeric
pharmaceutically acceptable materials for the purpose of improving the oral
delivery
of the API by improving the bioavailability of the API, extending the release
of the
API, targeting the release of the API to specific sites of the
gastrointestinal tract,
delaying the release of the API, or producing pulsatile release systems for
the API.
Dispersion of one or more APIs, wherein the API is a small organic molecule,
protein, peptide, or polynucleic acid; in polymeric and/or non-polymeric
pharmaceutically acceptable materials for the purpose of creating bioerodable,
biodegradable, or controlled release implant delivery devices.
Producing solid dispersions of thermolabile APIs by processing at low
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temperatures for very brief durations.
Producing solid dispersions of APIs in thermolabile polymers and excipients
by processing at low temperatures for very brief durations.
Rendering a small organic API amorphous while dispersing in a polymeric,
non-polymeric, or combination excipient carrier system.
Dry milling of crystalline API to reduce the particle size of the bulk
material.
Wet milling of crystalline API with a pharmaceutically acceptable solvent to
reduce the particle size of the bulk material.
Melt milling of a crystalline API with one or more molten pharmaceutical
excipients having limited miscibility with the crystalline API to reduce the
particle size
of the bulk material.
Milling crystalline API in the presence of polymeric or non-polymeric
excipient
to create ordered mixtures where fine drug particles adhere to the surface of
excipient particles and/or excipient particles adhere to the surface of fine
drug
particles.
Producing heterogeneously homogenous composites or amorphous
composites of two or more pharmaceutical excipients for post-processing, e.g.,
milling and sieving, which are subsequently utilized in secondary
pharmaceutical
operations well known to those of skill in the art, e.g., film coating,
tableting, wet
granulation and dry granulation, roller compaction, hot melt extrusion, melt
granulation, compression molding, capsule filling, and injection molding.
Producing single phase, miscible composites of two or more pharmaceutical
materials previously considered to be immiscible for utilization in a
secondary
processing step, e.g. melt extrusion, film coating, tableting and granulation.
Pre-plasticizing polymeric materials for subsequent use in film coating or
melt
extrusion operations.
Rendering a crystalline or semi-crystalline pharmaceutical polymer
amorphous, which can be used as a carrier for an API in which the amorphous
character improves the dissolution rate of the API-polymer composite, the
stability of
the API-polymer composite, and/or the miscibility of the API and the polymer.
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CA 2979451 2017-09-15
Deaggregate and disperse engineered particles in a polymeric carrier without
altering the properties of the engineered particles.
Simple blending of an API in powder form with one or more pharmaceutical
excipients.
Producing composites comprising one or more high melting point APIs and
one or more thermolabile polymers without the use of processing agents.
Homogenously dispersing a coloring agent or opacifying agent within a
polymer carrier or excipient blend.
In the following detailed description of preferred embodiments of the present
disclosure, reference is made to the figures in the drawings, in which the
same
numeral refers to an identical or similar part in different figures.
The present disclosure is directed to a novel thermokinetic mixer and mixing
process that can blend heat sensitive or thermolabile components without
substantial thermal degradation. In particular, the disclosure is useful in
processing
mixtures that include thermolabile components whose exposure to a melt
temperature or a cumulative heat input over a defined time period results in
degradation. One embodiment of present disclosure is directed to a method for
a
continuous melt blend of an autoheated mixture in the mixing chamber of a high
speed thermokinetic mixer, where a first speed is changed mid-process to a
second
speed upon achieving a first desired or predetermined process parameter. In
other
embodiments, the second speed is changed mid-process to a third speed upon
achieving a second desired or predetermined process parameter. Additional
speed
changes are also within the scope of the present disclosure, as dictated by
the
number of desired or predetermined processing parameters needed to produce the
desired composition or composite.
This process is especially applicable for producing solid dispersions of
thermolabile APIs by processing at low temperatures for very brief durations
at
multiple speeds, producing solid dispersions of APIs in thermolabile polymers
and
excipients by processing at low temperatures for very brief durations at
multiple
speeds, producing solid dispersions of APIs in thermolabile excipients by
processing
at low temperatures for very brief durations at multiple speeds, and producing
solid
dispersions of heat sensitive polymers by processing at low temperatures for
CA 2979451 2017-09-15
..
relatively brief durations at multiple speeds.
One embodiment is to use two or more different speeds during thermokinetic
processing of a batch to reduce required processing time after a shear
transition
temperature of a portion of the batch is reached. Another embodiment is to use
two
or more different speeds during thermokinetic processing of a batch to reduce
required processing time where the batch reaches a temperature whereafter a
substantial amount of heat generated by frictional contact with shaft
extensions
and/or an inside surface of the mixing chamber produces thermal degradation of
one
or more components of the batch, and reducing the speed. Yet a further
embodiment is to use two or more different speeds during thermokinetic
processing
of a batch to reduce required processing time where the batch reaches a
temperature whereafter a substantial amount of heat generated by frictional
contact
with shaft extensions and/or an inside surface of the mixing chamber does not
result
in an overall temperature change for the batch. Yet a further embodiment is to
provide a thermokinetic processing method using two speeds to reduce thermal
degradation of thermolabile or heat sensitive polymers or components of a
batch
processed thereby.
In one embodiment, at least a portion of a batch in the mixing chamber of the
high speed mixer comprises heat sensitive or thermolabile components whose
exposure to a limit temperature or limit of cumulative heat input over a
defined time
period must be substantially prevented or limited to obtain a melt blended
batch with
acceptable degradation of the heat sensitive or thermolabile components. In
this
embodiment, at least one of the speed changes between a start and end of the
process is made so that the limit temperature or limit of heat input is not
exceeded,
thereby preserving the heat sensitive or thermolabile components in the
composition
or composite.
Thermolabile components include, but are not limited to, thermolabile APIs,
excipients or polymers. Heat sensitive polymers include, but are not limited
to,
nylon, polytrimethylene terephthalate, polybutene-1, polybutylene
terephthalate,
polyethylene terephthalate, polyolefins such as polypropylene and high-density
or
low- density polyethylene, and mixtures or copolymers thereof, which polymers
can
be subject to surface and bulk polymer deficiencies as well as extrusion
limitations.
Other heat sensitive polymers include poly (methylmethacrylate), polyacetal,
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CA 2979451 2017-09-15
_
polyionomer, EVA copolymer, cellulose acetate, hard polyvinylchloride and
polystyrene or copolymers thereof. A limit temperature in the disclosed
process for
such heat sensitive polymers may be chosen by maintaining sensed temperature
of
a batch within an acceptable range from the well known degradation temperature
for
that polymer, such as about 5, 10, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70,
75, 80,
85, 90, 95, or 100 degrees Celsius from a temperature at which it is known in
the art
that heat sensitive polymers begin to undergo degradation of a desired process
parameter.
One embodiment of the present disclosure is a method for continuous
blending and melting of an autoheated mixture in the mixing chamber of a high
speed mixer, where a first speed is changed mid-processing to a second speed
upon achieving a first desired or predetermined process parameter. In one
embodiment, the second speed is maintained until a final desired or
predetermined
process parameter is achieved, whereupon shaft rotation is stopped and a melt
blended batch is withdrawn or ejected from the mixing chamber for further
processing. The shaft operates at one or more intermediate rotational speeds
between changing to the second speed and stopping the shaft rotation. Process
parameters which determine shaft speed changes are predetermined and may be
sensed and displayed, calculated, inferred, or otherwise established with
reasonable
certainty so that the speed change(s) is made during a single, rotationally
continuous processing of a batch in a mixing chamber of the high speed mixer.
Process parameters include without limitation temperature, motor RPM, amperage
draw, and time.
This disclosure is also directed to a thermokinetic mixer that can blend heat
sensitive or thermolabile components without substantial thermal degradation.
One
embodiment of the thermokinetic mixer has a high horsepower motor driving the
rotation of a horizontal shaft with teeth-like protrusions that extend outward
normal to
the rotational axis of the shaft. The shaft is connected to a drive motor. The
portion
of the shaft containing the protrusions is contained within an enclosed vessel
where
the compounding operation takes place, i.e., a thermokinetic mixing chamber.
The
high rotational velocity of the shaft coupled with the design of the shaft
protrusions
imparts kinetic energy onto the materials being processed. A temperature
sensor
senses the temperature within the thermokinetic mixing chamber. Once a set
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CA 2979451 2017-09-15
temperature is sensed, a first speed is changed to a second speed.
FIG. 1 shows a view of one embodiment of the disclosed thermokinetic mixer
assembly. A temperature sensor 20 is connected to a thermokinetic mixing
chamber
MC. The temperature sensor 20 provides information to a programmable logic
.. controller 20a which appears on a programmable logic controller display
20b. A
drive motor 15 controls the speed of the shaft which rotates through the
mixing
chamber MC. The drive motor 15 is controlled by a variable frequency drive
20c.
The variable frequency drive 20c also provides information to the programmable
logic controller 20a which appears on the programmable logic controller
display 20b.
When a desired process parameter is met, the programmable logic controller 20a
signals the variable frequency drive 20c to change the frequency of the
electrical
power supplied to the drive motor 15. The drive motor 15 changes the shaft
speed
of the shaft. The temperature sensor 20 can be a sensor to radiation emitted
from
batch components.
FIG. 2 shows an exploded view of one embodiment of the thermokinetic
mixer. A frame 1 supports associated components such that a shaft assembly 2
is
inserted in an axis of a shaft hole through end plate 3 and a feed screw hole
through
end plate 4, the two end plates defining enclosing ends of a mixing chamber
cylinder, the bottom portion of the cylinder defined by the inside surface of
the lower
.. housing 5. Lower housing 5 comprises a dropout opening closed off during
operation with discharge door 6. The upper housing 7 comprises an upper part
of
the cylinder of the inside surface of the mixing chamber. The feed housing 8
is
adapted to permit feeding of material to the feed screw of the shaft assembly
so that
such material is, in combination with the feed screw rotation, compressingly
forced
.. into mixing chamber from an external feed. Door 6 rotatably closes about
discharge
door pivot pin 9. End plate 3 has attached to it a rack & pinion cylinder 18
with
spacer 10 interposed. At the top of housing 7 is mounted a bracket 11 with
which to
support an infrared temperature sensor 20 for the mixing chamber. Door guard
12
protects the sometimes high temperature door 6 from accidental human contact
with
dropout material. Rotary guard 13 and drive coupling guard 14 guard human
operators from contact with rotating components during operation. Drive motor
15 is
preferably an electric motor with sufficient power to accomplish the disclosed
operation. The pillow blocks 16 and 17 support the shaft assembly 2.
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CA 2979451 2017-09-15
In an example of a system in which the process parameters that determine
shaft speed changes are measured in the mixing chamber and/or drive motor,
FIG.
7 shows a block flow diagram of the disclosed process where a mixing chamber
MC
is connected by a shaft to a drive motor 42, where a variable frequency drive
41
controls the rotational speed of drive motor 42. In certain embodiments, shaft
speed
can be from 0 through 5000 RPM. Further, a programmable logic controller 40
determines and carries out a change in rotational shaft speed using a variable
frequency drive 41 according to the disclosed process. The programmable logic
controller 40 comprises setpoints entered by a user for determination of a
need for
changing a rotational shaft speed in drive motor 42 and to transmit to the
variable
frequency drive 41 a command to change such speed after rotational processing
of
the batch load has been added to the mixing chamber. The programmable logic
controller may incorporate a microprocessor comprising memory incorporating a
control program adapted to act upon achievement of setpoints entered by a user
relying on sensor data transmitted from drive motor 42 and/or mixing chamber
MC,
and include a user interface such as a programmable logic controller display
for a
user to observe operating time and/or sensor data transmitted from drive motor
42
and/or mixing chamber MC. The programmable logic controller optionally
comprises
a method for a user to directly change motor shaft speeds upon consideration
of
predetermined process parameters (such as operation time) or upon comparison
of
predetermined process parameters with sensor data transmitted from drive motor
42
and/or mixing chamber MC (such as batch temperature, amperage draw, and shaft
speed). The programmable logic controller optionally comprises an automated
control method to change motor shaft speeds upon microprocessor operation at
predetermined, stored process parameters (such as operation time) or upon
comparison of predetermined, stored process parameters with sensor data
transmitted from drive motor 42 and/or mixing chamber MC (such as batch
temperature, amperage draw and shaft speed).
A description of components of one embodiment of a thermokinetic mixer for
the disclosed process is shown in FIGS. 3 and 4. Figure 3 shows a shaft-radial
cutaway view of a mixing chamber MC for a thermokinetic mixer of the
disclosure
with halves 5 and 7 joined to form a cylindrical mixing cavity having shaft 23
rotating
in rotation direction 24 in an axial length of the chamber. Shaft extensions
30
34
CA 2979451 2017-09-15
extend from their releasable connection on shaft 23 to a position near an
inside
surface 19. Shaft extension 30 comprises top face 22 and front face 21.
Particles
26a-26e show impingement of such particles on shaft extension 30 and on inside
surface 27, which impingement causes comminution and/or frictional heating of
the
particles by the shear generated by such impingement. Further, FIG. 4 is an
exploded view of the extensions and mixing chamber shown in FIG. 3, where
shaft
extensions 30a, 30b, and 30c each having a top face 22 and a front face 21
defined
upon a replaceable tooth which is adapted to be secured to foot section 31 by
bolt
33. Section 311s adapted to be replaceably fixed to shaft 23 (continued from
motor
shaft 34) at slot 35 by way of bottom section 32 of section 31. FIG. 4 shows
that
particles are generally moving in direction 37 when they encounter shaft
extensions
30a to 30c. Shaft extension 30a is shown having its front face 21 aligned
effectively
opposing those of shaft extensions 30b and 30c.
With a typical batch process, a user will first select two components, which
could include, for example, a thermolabile API and a polymer excipient. The
user
will then empirically determine the shear transition temperatures of the two
components. The user will then set the process parameters (temperature, RPM,
amperage draw, and time) in the programmable logic controller to change from
the
first speed to the second speed as is suitable for the shear transition
temperatures
of the components. Any of the setpoints entered by the user can be used as a
stop
point following the period of the second speed.
FIG. 5 shows certain potential differences between the methods of the
present disclosure, and that of a thermokinetic mixing method using a
substantially
single shaft speed. FIG. 5 shows a graph of batch sensed temperature, shaft
rotational speed in RPMs, and amperage draw on the motor as a directly
proportional measure of energy input into the batch at any moment in the
processing. As a specific example the following composition was
thermokinetically
processed to form a batch of Griseofulvin : PVP (1 : 2 ratio) at a batch size
of 60
grams. Griseofulvin represents a thermolabile API. PVP represents an
excipient. A
series of three tests is represented in FIG. 5 and was conducted in a
thermokinetic
mixer similar in construction to that shown in FIGS. 3 and 4, where front
faces 21
project in a forward rotation direction with a side to side width of about 1.0
inches
and are maintained at about 30 degrees away from a plane extending from an
axis
CA 2979451 2017-09-15
of the shaft 23 through a leading edge of the front faces 21 with a height of
about
2.5 inches. The batch in FIG. 5 was processed under thermokinetic, autoheating
conditions in which a substantially single shaft speed was used. The y-axis is
applicable to temperature (values times 10) and shaft speed in RPM (value
times
30). Time on the x-axis is in increments of 0.10 seconds. If the composition
of this
batch were thermokinetically mixed at rotational shaft speeds substantially
higher
than that shown in FIG. 5, i.e., at 2500 RPM and higher, inspection of the
final
product showed that it was unacceptably crystalline and insufficiently
amorphous.
This result would be unexpected to one of skill in the art. Higher shaft
speeds are
.. taught in the thermokinetic mixing art to assure better mixing, which did
not occur at
higher shaft speeds with these materials. When the example batch composition
was
processed as shown in FIG. 5, at lower rotational shaft speed, inspection of
the final
product showed that it was sufficiently amorphous and adequate for
bioavailability.
However, unacceptable thermal degradation of the thermolabile API occurred,
which
rendered the batch unacceptable.
In FIG. 5, at time zero, amperage draw immediately increased to 35 amps
(1050 on the graph). Ejection of the batch was at about 17.6 seconds or where
RPMs are shown to significantly decline. The rotational shaft speed was set
for
1800 RPMs and reached that speed within about 2 seconds from start. Within
about
7 seconds, the batch temperature reached 260 F, the shear transition
temperature
for the excipient. Above the shear transition temperature, the excipient's
resistance
to shear significantly decreased and energy delivered to the batch by
impingement
of particles and molten material on the extension surfaces and inside surface
of the
mixing chamber consequently also significantly decreased (the amperage draw
.. dropped to about one half when the shear transition temperature was reached
in the
batch temperature). From about 7 seconds to 16 seconds, the batch temperature
of
the composition was not rising while substantial energy continued to be
absorbed by
the batch. Such energy that did not result in increased temperature translated
to
thermal degradation of the thermolabile or heat sensitive components. This
test
confirms in general that once a significant amount of a component, i.e.,
greater than
5 weight percent, 10 weight percent, 20 weight percent, or 30 weight percent,
in a
thermokinetically melt blended batch reaches its shear transition temperature
or
melting point, a substantial amount of heat absorbed by the entire batch
results in
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CA 2979451 2017-09-15
thermal degradation of thermolabile or heat sensitive components instead of
increasing overall batch temperature. This is clearly shown in the time range
from 7
through 16 seconds in FIG. 5, where batch temperature actually decreased with
continuous energy input to the batch.
The same batch and thermokinetic mixer in FIG. 5 were used in FIG. 6, but
two speeds were implemented through the continuous rotational batch
processing.
In FIG. 6, a programmable logic controller connected to an infrared sensor and
a
variable frequency drive was used for detecting a batch temperature, comparing
the
batch temperature to a predetermined setpoint, and automatically changing
rotational shaft speed of the thermokinetic mixer to another speed for the
duration of
the process until the batch was released by way of opening a bottom dropout
door.
A first speed was set for 1800 RPM and a second speed was set for 2600 RPM.
The predetermined setpoint for the batch temperature was chosen to be 200 F as
a
substantial level below the excipient shear transition temperature. In a
preferred
embodiment, a speed change may be effected before a substantial component's
shear transition temperature is reached, and the system requires response time
between the moment a sensed batch temperature is transmitted to the
programmable logic controller and the shaft speed actually is changed. As
shown in
FIG. 6, no substantial energy input to the batch was diverted from overall
batch
temperature increase. The processed batch showed substantially complete
amorphosity and no detectable thermal degradation of the API with an overall
processing time of about 6.5 seconds. This time stands in dramatic contrast to
that
of the processing time of that in FIG. 5 at 17.6 seconds.
FIG. 6 indicates that shaft rotational speed for certain thermolabile
components should be substantially increased at or before a substantial
component
or portion of a thermokinetically batch reaches a shear transition temperature
or
melting point, whereafter processing time should be minimized. In certain
embodiments, a first speed should be increased by about 100 RPM, 200 RPM, 300
RPM, 400 RPM, 500 RPM, 600 RPM, 700 RPM, 800 RPM, 900 RPM, 1000 RPM, or
more to a second speed. In other embodiments, a processing time after the
second
speed starts until the batch is released from the mixing chamber should be
about 5
percent, 10 percent, 15 percent, 20 percent, 25 percent or more of the total
time the
batch was processed at the first speed.
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CA 2979451 2017-09-15
It is well known in the art that impact of a particle on a surface imparts
energy
to the particle. It is a feature of thermokinetic, auto-heating mixers to
provide impact
on a particle containing polymers whereby imparted energy is translated partly
into
heat energy to soften and/or melt those polymers. However, the thermokinetic
mixing art generally directs those skilled in the art to provide impact for
particles in
thermokinetic mixers in a manner that lacks fine control of translation of
impact
energy into heat energy. The present disclosure provides for and describes
methods for such control. Highly cross-linked polymers and thermoset compounds
are highly refractory to softening and melting for the same reason they are
preferred,
i.e., they resist breaking down. Yet, they are shown to be of value in some
combinations of components processed with thermokinetic mixing. Indeed,
thermokinetic mixing is essentially the only way to process highly cross-
linked
polymers and thermosets due to their resistance to melting and blending in any
other
manner. In the thermokinetic mixing art, increasing rotational shaft speed
and/or
processing time were understood to be the method by which melt-resistant
polymers
could be induced to translate sufficient impact energy to heat energy to
effect a
softened or molten state for further processing. The present embodiment
discloses
an apparatus and methods by which impact energy translation to heat energy can
be
effectively controlled.
Two primary impact surfaces, the front face and the top face of a shaft,
control impact translation to heat energy in a thermokinetic mixer. Those two
surfaces are the facial portions of the shaft extensions that intrude into the
outer 30
percent or less of volume of the mixing chamber (the volume is referred to
hereafter
as the "main processing volume"; it includes a most restricted zone of about
one
inch inward radius from the inside cylindrical wall of the mixing chamber) and
the
inside cylindrical surface of the mixing chamber itself. Changing the inside
cylindrical surface of the mixing chamber is not a practical option ¨ that
surface,
being stationary, must remain smooth and cylindrically uniform to resist
buildup of
molten materials and to allow for skidding and sliding autoheating contact
with
particles being moved through the mixing chamber.
The present disclosure uses variations in the top face of the shaft extensions
that intrude into the main processing volume to control translation of
rotational shaft
energy delivered to the extensions into heating energy within particles
impacting the
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CA 2979451 2017-09-15
portions. It has been found that varying the width and angle away from a shaft
axis
plane for the main facial portion provides a controllable variation in shear
delivered
to a particle impacting the portion, which in turn provides control over shaft
energy
translated into heat energy available for softening or melting a polymer part
of a
particle in a thermokinetic mixing chamber.
Referring again to FIGS. 3 and 4, it has been found that providing particles
within the mixing chamber a cumulative experienced shear which is determined
by
the shape and dimensions of a rotation-directed facial surface of extensions
from
the shaft and the inside surfaces of the mixing chamber results in the
autoheating
phenomena of thermokinetic mixing. Substantially all the particles within a
mixing
chamber during shaft rotation inhabit the outer 30 percent of the volume of
the
internal space, i.e., the centrifugal force of the rotation of the extensions
maintains
the particulates and molten materials away from a central volume of the mixing
chamber. Thus, the effective thermokinetic mixer must be designed so that
distal
.. end parts of the shaft extensions are formed to accomplish the three
functions of
direct high shear (on the end part front face of the extension), indirect high
shear (on
the inside surfaces of the mixing chamber), and centrifugal maintenance of
material
in the outer volume of the mixing chamber. The top faces of shaft extensions
30a to
30c form a substantially vertical rectangle arranged at an angle away from a
plane
passing through an axis of shaft 23. It has been found that changing the
width,
angle, or varying the shape of the simple rectangle or arcuate paddle of the
shaft
provides an unexpected improvement and control over cumulative shear delivered
to
particles within a mixing chamber of a thermokinetic mixer, which, in turn,
provides
control over imparted heat energy and desired heat input to heat sensitive or
thermolabile components in a processed batch.
For these specific comparisons of the operation of thermokinetic mixers with
several configurations of a main facial portion, it is assumed that energy
input
through the shaft and the shaft rotational speed is about the same and that
the
number of shaft extensions and their spacing along the length of the shaft
within the
mixing chamber is substantially the same. Thus, the comparisons will show the
effect of changing the shapes of the main facial portion.
In general, decreasing the width relative to the length of the main facial
portion increases shaft energy translated into heat energy available for
softening or
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CA 2979451 2017-09-15
melting a polymer part of a particle in a thermokinetic mixing chamber. The
width
must be above a minimum contact width so that a particle experiences a sliding
impact along the width, the particle is induced into a "skid" or energy
imparting
frictional contact, rolling and sliding at the period of time for impact on
the portion.
Mere normal glancing impact of a particle on a surface is relatively
ineffective in
imparting thermokinetic, autoheating energy for softening or melting. Yet,
easily
melted and heat-labile or heat sensitive polymers in some cases are sometimes
processed with a main facial portion providing just such glancing impact to
provide
more control over heat application to such components. Consistent with this
teaching, polymers refractory or resistant to softening or melting by
application of
heat are often processed with a main facial portion of minimum width (at least
0.25
inches) aligned at a minimum angle back from a shaft axial plane (for example,
at
least 10 degrees or at least 15 degrees) providing a contact time for
essentially the
same energy input, whereby distribution of that energy into skidding and
rotational
motion improves autoheating of the particle's polymer content.
A design of a shaft extension currently found in the Draiswerke Gelimat
thermokinetic mixer has the cross section 50 shown in FIG. 8, having a rounded
main facial portion 51 and an overall substantially spiral shape with a width
of about
2 inches. Relative shear 52 shown in a number of shortened arrows directed at
the
main facial portion 511s not substantial for this design. Thus, this device
has been
relatively costly in terms of increased processing time and shaft power to
generate
sufficient thermokinetic heating to melt-blend polymers with substantial
resistance to
softening or melting. As such, it is relatively inadequate for processing heat
labile or
heat sensitive polymers having such resistance. There has been no suggestion
in
the thermokinetic mixing art that changing the width or angle of the main
facial
portion relative to a shaft axial plane would have any affect on thermokinetic
processing of polymers. The present disclosure discloses such embodiments in
FIGS. 9 through 12.
FIGS. 9 through 12 respectively show main facial portion cross sections 53
through 56 having main facial portions 57 through 60 with identical widths at
angles
of about 15 degrees, 30 degrees, 45 degrees and 60 degrees back from a shaft
axial plane for the extensions which they represent. The projected widths on
that
shaft axial plane of main facial portions 57 through 60 are shown respectively
in
CA 2979451 2017-09-15
lengths 65 through 68 and are directly related to relative shears 61 through
64,
where an increasing angle of a main facial portion relative to a shaft axial
plane with
identical width decreases the projected width onto the plane and unexpectedly
increases relative shear for the same shaft power input, rotational shaft
speed and
extension spacing and arrangement on the shaft. With this disclosure, it is
now
possible to control autoheating by delivered shear in the extensions of a
thermokinetic mixer. Decreasing the widths of main facial portions while
maintaining
the angle relative to a shaft axial plane maintains total heat input into a
thermokinetically processed batch in the mixers but increases shear upon any
individual particle by reducing projected length along the shaft axial plane.
Thus, the shear strength of polymers processed by way of thermokinetic,
autoheating mixing and blending can now be matched to the relative shear
energy
imparted by the shaft extensions in the mixing chamber. A further design
refinement
is desirable where, as is quite common, polymer components in a batch comprise
both high shear and low shear polymers. Providing a main facial portion suited
for a
high shear component imparts shear energy which may deliver too much heat
energy to low shear components. In such a case, the low shear component tends
to
soften and roll along the width of the main facial portion, further increasing
the heat
generated, while the high shear components tend to leave that surface more
readily.
Such a circumstance could tend to cause incomplete mixing with the high shear
components insufficiently melted or overheating of low shear components. There
is
yet a further need for designs of a main facial portion that achieve an
optimal shear
delivery to high and low shear components in a thermokinetic batch.
It has been found that increasing the width of the main facial portion
achieves
this optimization. At an angle of between 15 to 80 degrees from a shaft axis
plane,
and the main facial portion having a width of at least 0.75 inches, provides
sufficient
path travel for both high and low shear polymer components in a batch so that
the
high shear components remain in sliding and skidding contact with the main
facial
portion long enough to generate heat and absorb heat from lower shear
components
to become softened and thereby blend with the low shear components.
Alternate designs for the main facial portion are shown in FIGS. 13 through
17, respectively, showing main facial portion cross sections 69, 72, 76, 80,
84, and
87. FIG. 13 shows cross section 69 comprising a leading acute surface 70
41
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extending rearward to obtuse surface 71, providing a first low shear surface
followed
by a higher shear surface. FIG. 14 shows cross section 72 comprising a leading
acute surface 73 extending rearward to 90 degree surface 74, which in turn
extends,
rearward to tailing acute surface 75, providing a first low shear surface
followed by a
higher shear surface and a lower shear surface. FIG. 15 shows cross section 76
comprising a leading acute surface 77 extending rearward to obtuse surface 78,
which in turn extends rearward to tailing acute surface 79, providing a first
low shear
surface followed by a higher shear surface and a lower shear surface. FIG. 16
shows cross section 80 comprising a leading obtuse surface 73 extending
rearward
.. to acute surface 74, which in turn extends rearward to tailing obtuse
surface 75,
providing a first high shear surface followed by a lower shear surface and a
high
shear surface. FIG. 17 shows cross section 84 comprising a leading and rising
arcuate surface 85 extending rearward to a tailing and reducing arcuate
surface 86
degree surface 74, which in turn extends rearward to tailing acute surface 75,
.. providing a first low shear surface followed by a higher shear surface and
a lower
shear surface. FIG. 18 shows cross section 87 comprising a leading acute
surface
88 and a tailing acute surface 89, providing a first low shear surface
followed by a
higher or lower shear surface, depending on the shear of the batch components.
In light of the above teaching of these embodiments, the top face 22 of FIG. 4
is a significant element in providing thermokinetic contact with particles in
the mixing
chamber and causing them to impact the inside cylindrical surface of the
mixer.
FIG. 19 shows another significant embodiment of the thermokinetic mixer of
the present disclosure, in that halves 5 and 7 and door 6 are respectively
interiorly
lined by interior liner pieces 5a, 7a and 6a. The liner pieces are adapted to
intimately lie adjacent to inside surfaces of halves 5 and 7 and door 6 during
operation of the mixer, thereby providing any of a diverse set of
thermokinetic
frictional contact surfaces desired for accelerated particles, such desired
surfaces
selected from among any appropriate or optimized materials for liner pieces
5a, 7a
and 6a. FIG. 19 shows in exploded view the liner pieces 5a, 7a and 6a
separated
.. from their adjacent (as installed) parts. Bolting the halves 5 and 7
together cause
liner pieces 5a and 7a to secure to line the inside surfaces of those halves 5
and 7.
Holes in end sections of liner piece 6a allows for bolted connection of it to
door 6. In
thermokinetic mixers known to those of skill in the art, the inside surfaces
of the
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mixing chamber were limited to those steel alloys with sufficient mechanical
and
thermal strength required for encasing and enclosing the thermokinetic
operation of
such mixers. Therefore, known thermokinetic mixers were limited in their
processing
capabilities to only those mixtures which would not excessively adhere to a
smooth
inside surface of steel alloy of the mixing chamber and which, at the same
time,
would impinge beneficially on those surfaces to provide frictional heating of
particles
in the mixture. Further, even relatively slight wear on the inside surfaces of
the
mixing chambers of thermokinetic mixers can significantly alter the efficacy
of the
generation of thermokinetic heating of chambered particles, in that the
distance
between the shaft extensions and the inside surface of the mixing chamber is
specifically designed to optimize thermokinetic heating by the interaction of
particles
moving between the inside surface of the mixing chamber and the shaft
extensions.
Thus, such slight wear can require that the entire, relatively expensive set
of halves
5 and 7 to be replaced in such thermokinetic mixers. The present embodiment
eliminates such excessive cost. Liner pieces 5a, 7a and 6a are relatively much
less
in cost to replace than halves 5 and 7 and door 6. Replacement of the liner
pieces
is quite simple and fast. Preferred liner piece composition includes stainless
steel
(alloys with greater than 12 weight percent chrome) and other such steel
alloys,
titanium alloys (such as nitrided or nitride-containing titanium), and wear
and heat
resistant polymers (such as Teflon ). It is another embodiment of the present
disclosure to provide non-smooth inside surfaces for liner pieces 5a, 7a and
6a,
such as parallel or spiral grooving about the inside cylindrical surfaces of
liner pieces
5a, 7a and 6a, surface texturing, and/or electropolishing. Such materials and
texturing for liner pieces 5a, 7a and 6a are intended to obtain an optimum or
desirable balance of characteristics which will reduce undesirable adhesion of
thermokinetically melted particles and/or promote thermokinetic frictional
contact of
mixing chamber particles in their travel among the shaft extensions and the
inside
surfaces of the liner pieces 5a, 7a and 6a.
In a further embodiment of the present disclosure whereby materials or
texturing of liner pieces 5a, 7a and 6a are selected to obtain the objects of
thermokinetic mixing, shaft extension portions comprising the front and top
impact
faces of the shaft extensions are adapted by way of material composition
and/or
texturing similar to those changes just disclosed for the inside surfaces of
liner
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pieces 5a, 7a and 6a.
Another feature of the present disclosure is that the top face of the shaft
extensions, i.e., those which extend at least with a slight elevation rearward
above
the height of the front face of the shaft extension to form a ramp structure
upon
which chambered particles impinge (faces 22 of FIGS. 3 and 4), are the primary
location of wear among the inside surfaces of the mixing chamber. The
consequences of this discovery are considerable with respect to the design of
shaft
extensions in thermokinetic mixers. It has been found that such a top face has
a
function very different than that of the front face. A front face of a shaft
extension
drags a particle along its rearward directed width, causing the particle to be
driven
substantially in a direction of an axis of the drive shaft. Such an axis-
driven particle
will then tend to engage yet another front face of a shaft extension of a
rearward and
next line of shaft extensions. The motion of particles in contact with a top
face of a
shaft extension driven by shaft rotation is very different, imparting in such
motion a
substantially greater frictional, thermokinetic energy to a particle than the
front face
of the shaft extension.
FIG. 20 shows a side view (a view in the direction of the axis of a shaft to
which it is mounted) of a removable portion of a shaft extension 30 showing a
front
face 21 and top face 22. Reference elevations 30b to 30d are measured from a
base level 30a. Neither front face 21 or top face 22 are shown in plan view
but
rather are shown with their projections upon the side shaft-axial view. Top
face 22
comprises a front edge rising from elevation 30c to 30b and thereafter
sweeping
rearward and upward to similarly inclined rear edge with a highest elevation
30d.
Only a part of the inside surface of half 7 is shown as separated from top
face 22
and portions P1 to P4 represent the path of a particle impinging first upon
top face
22 and then upon the inside surface of half 7. It has been found that the area
of
greatest wear on any inside surface of the mixing chamber is along the
rearward
area from the front edge represented by the line from elevations 30c to 30b,
i.e., the
impact point of a particle at portion P1. A major portion of kinetic energy is
clearly
translated to frictional heating to the particle in that area as evidenced by
the
substantial wear on such hardened surfaces. Top face 22 rises more rapidly at
its far
edge along elevations 30b to 30d than along the near edge starting at
elevation 30c,
resulting in a relatively long frictional travel path of the particle along
portion P2 and
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being ramp-launched from elevation 30d toward the inside surface of half 7.
Upon
frictional, spinning, and dragging contact with the inside surface of half 7
at portion
P3, the extensively heated particle rebounds from the inside surface of half 7
to
again contact a top face of another shaft extension. The length of portion P2
substantially controls required frictional heating time for thermokinetic
mixing and
melting for a batch of particles within the mixing chamber of the present
disclosure.
The present disclosure comprises selecting a shaft extension which provides to
an
impinging particle in thermokinetic mixing a top face contact path of longer
or shorter
length and angle of deflection to thereby control a substantial or majority of
frictional
heating contact of chambered particles to a desired batch temperature.
FIG. 21 shows a perspective view of a specific embodiment of the shaft
extension of FIG. 20 having a concave front face 21 and a top face 22 capable
of
producing variable lengths of portions P2' (longer) and P2" (shorter)
respectively for
portions P3' and P3". In certain embodiments, the top face 22 comprise a
convex
surface with a radius of about 4.5 inches extending from its front, leading
edge to its
rearmost edge.
In certain embodiments, a shaft extension providing a relatively long
frictional
contact path for particles being processed by the mixer of the present
disclosure are
preferred for providing shortened processing times, i.e., to heat a batch to a
desired
temperature as quickly as possible. Such control of heating and processing
times is
directly applicable to the disclosed process of two step continuous
thermokinetic
mixing, whereby increasing rotational shaft speed will more swiftly impart
frictional
heating for melting energy to the particles more refractory or resistant to
lower speed
heating. It has been found that non-uniformity of materials in a batch
processed
thermokinetically, i.e., either by composition or particle size, results in
greater or
lesser frictional path contact with the insides of the mixing chamber.
Particles more
resistant to melting, either by way of higher melting temperatures or
hardness, will
rebound more quickly from frictional contact with the inside surfaces of a
thermokinetic mixer and thereby require more processing time than less
refractory
particles. Thermokinetic mixing to a final, desired processing consistency for
heat
labile or heat damageable components generally favors reaching a target batch
temperature as quickly as possible. Certain embodiments of the present
disclosure
provide short, medium, long or mixed lengths of particle frictional contact
paths
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along a top face of a shaft extension, either by way of a single or multiple
processing
shaft speeds, to achieve the more effective mixing of certain thermolabile
components.
It is well known to those in the art that the topmost surfaces of shaft
extensions in the Draiswerke mixers are merely arcuately tapered and smoothed
ends of a generally sinous shaft extension. As such, the ability of such
mixers to
provide substantial top face shearing, frictional heating to thermokinetic
mixing
chamber particles is essentially minimized. To accomplish additional top face-
like
frictional paths for particles in the mixing chamber and to accomplish other
objects of
the present disclosure, FIG. 22 discloses a frontal view of an OPEN 30 shaft
extension having a central OPENING so that particles can pass through it
during
processing and impinging on identically rearwardly angled pairs of surfaces
A1/A2,
B1/B2 and C1/C2. It will be appreciated that surfaces A1/A2 together act upon
particles as a top face and that surfaces B1/B2 and C1/02 act upon particles
as
front faces. FIG. 22 more generally discloses that shaft extensions may be
formed
in a donut or toroid shape or in the shape of a diamond with a central opening
to
accomplish the more effective mixing of certain thermolabile components.
Detailed Description of the Invention for the First and Second Embodiments
FIG. 23 is a general mechanical diagram for the processes of the first and
second embodiments. In, FIG. 23 shows a mixing chamber MC comprises a
temperature sensor or Raman spectroscopy probe 20 (as described above),
situated
in the mixing changer MC so as to detect respectively average mixing batch
temperature or to transmit laser to and collect recovered emissions from a
small
sample space for detection of a sample crystallinity by way of Raman
spectroscopy.
Probe 20 transmits its detected data to the optional Raman spectroscope and
device
microprocessor RS / DMC (when probe 20 is a Raman spectroscopy probe) or
directly to mixer control microprocessor MCM, which comprises a microprocessor
with memory and an input/output unit, said input/output unit is connected with
a user
interface comprising input buttons and an output display. Mixer control
microprocessor MCM operates under a mixer control program stored, which acts
to
receive and store detected trigger data from probe 20 and to thereafter
control shaft
speed of the thermokinetic mixer shaft motor and speed controller 15. The
mixer
control program comprises means for comparing detected trigger data or trigger
data
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rates calculated from the trigger data and compare absolute values of trigger
data or
trigger data rates with pre-determined trigger setpoints. Upon detection that
a trigger
data or trigger data rate has equaled or passed a trigger setpoint, the mixer
control
program acts to increase a speed of the mixer motor shaft or to terminate
mixing
after it has started.
Additional information about the physical and thermal changes that occur in
the first and second embodiments is now described. FIG. 6 shows trigger data
of
temperature versus mixing time for a component combination, where a plateau of
temperature extends from about 12 s. to about 52 s., referred to herein as the
plateau period. It was thought at the time of that experiment that the plateau
period
was necessary to obtain a desired level of thermokinetic mixing and reduction
of
pharmaceutical or drug crystallinity. The present inventor has discovered that
the
entire plateau period may not be needed or it may be used as the trigger
setpoint for
increasing motor shaft speed from a first, lower shaft speed to a second,
higher
shaft speed may either be a predetermined decrease in batch temperate rate, an
absolute value of detected crystallinity or a rate of declining crystallinity,
which
almost eliminates the plateau period in required thermokinetic mixing for
component
combinations.
In a slow second stage embodiment of the invention, it is preferred that a
first
stage be completed at plateau detection followed by a second stage at a lower
shaft
speed, whereby a final required reduction of crystalline form pharmaceutical
or drug
is accomplished at a reduced shear and friction intensity. The following are
components for which the slow second stage embodiment have been found
successfully applied: [pharmaceutical and excipient / carrier names].
A subtle difference in the effects of thermokinetic mixing on the component
combination must be appreciated as to a first step of a lower shaft speed and
a
second step of a higher shaft speed. It is now clear that the lower shaft
speed step
provides an amount of heat almost instantly at from 9-11 s. (FIG. 6) at a
lower batch
temperature (referred to herein as the first stage period) than the higher
batch
temperature achieved by thermokinetic mixing at a higher shaft speed,
resulting in
changing from 20-90% of the pre-mixing crystalline pharmaceutical into an
amorphous form, which is a substantial portion of the desired crystallinity
change.
But the lower shaft speed mixing provides substantially less kinetic energy
per unit
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of time to the mixing batch than the kinetic energy of the higher shaft speed
mixing,
resulting a temperature plateau as the crystalline components require ever
greater
energy per unit of remaining crystalline components to achieve conversion of
crystals to amorphous structures.
Elimination of the long plateau period, where degradation can occur of
desired drugs or pharmaceuticals, is a primary object of the first and second
embodiments, where degradation of even 0.2 percent of a desired pharmaceutical
or
drug can render a thermokinetically mixed batch not usable. In a specific
example,
one component combination required 18 seconds of a single, low speed
thermokinetic mixing, where, by using a pre-determined temperature increase
rate
as a trigger setpoint as the end of the first stage period to start a second
stage of
higher shaft speed, the required entire process time was 8 seconds. It is
preferable
that the second, higher shaft speed is from 20 to 100 percent greater than a
first,
lower shaft speed and more preferable that the second, higher shaft speed is
from
40 to 80 percent greater than a first, lower shaft speed.
Further, in general the pharmaceutical or drug of a component combination is
a small molecule as compared with its excipient, where the smaller, amorphous
molecule of the drug acts essentially as a "lubricant" for the much larger
polymer.
The energy input per unit of component combination is not high enough to
complete
a desired change from crystalline to amorphous structure until the "lubricant"
drug is
captured into the molten or "sticky" larger polymer aggregations. A useful
analogy is
that creating solid dispersions is like dissolving a drug in a liquid. To help
the drug
dissolve faster, either the temperature or the stirring rate should be
increased. It was
unpredictable that such a significant effect could be obtained in the first or
second
embodiments by detection of a process point at which the motor shaft speed
should
be increased to prevent drug degradation.
Returning to the first embodiment using a temperature increase rate as a
trigger setpoint, is fixed so that it passes through a port in mixing chamber
MC with a
distal end pointing generally toward the shaft supporting the shaft
extensions, where
another end of sensor 20 is connected to a batch microprocessor BMCRO. Batch
microprocessor BMCRO (comprising a CPU, a memory, a clock, and an input/output
unit, all operating under under a batch control program) receives sensed
temperature signals from sensor 20 and stores them its memory correlated to a
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recording time a predetermined intervals (preferably from 500 to 5 ms.),
whereupon
the batch control program causes the stored temperature and recorded time data
to
be used to calculate a rate of temperature change over a period of time from 2
s. to
ms. using an arithmetical average, differential rate of change calculation, or
other
5 averaging calculation method. A when a calculated rate of temperature
change is
determined to equal or to approach a predetermined trigger value of rate of
temperature change stored in the memory, the batch control program acts
immediately or with some delay to send a signal to a speed controller of motor
15 to
increase a lower shaft rotation speed to a higher shaft rotation speed,
preferably for
10 a predetermined period of time, whereafter the batch control program
acts to cause
motor 15 to stop.
FIG. 24 describes the steps of the alternate embodiment of the present
invention, where at step 102 a batch comprising a component combination is
added
to a batch chamber of a thermokinetic mixer specially designed for such
processing
and the shaft motor is started at a first, lower shaft rotation speed. At step
104, a
temperature sensor or Raman spectroscopic probe (with its Raman spectroscope)
sends signals to mixer control microprocessor for memory storage as trigger
data.
For the first embodiment, the mixer control microprocessor continuously
calculates from temperature trigger data a temperature rate of increase and
stores
those values in memory, calculating certain rates at step 106. The mixer
control
microprocessor comprises either a pre-stored value of a trigger setpoint of a
temperature increase rate or a trigger setpoint calculated by obtaining a
maximum
rate of increase over a previous period of time (which is preferably between
0.5 s.
and 1.0 s.) and calculating a trigger setpoint as a temperature rate of
increase which
is substantially less than that trigger setpoint.
For the second embodiment, the mixer control microprocessor continuously
stores crystallinity values detected in the mixing chamber as trigger data and
optionally at step 106 calculates a crystallinity rate of decrease and stores
those
values in memory. The mixer control microprocessor comprises either a pre-
stored
value of a trigger setpoint of a crystallinity value or a crystallinity
decrease rate as a
trigger setpoint.
At step 108, the mixer control program microprocessor determines if a trigger
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setpoint has been reached by trigger data or their calculated rates. If that
state
occurs, the mixer microprocessor acts to either increase shaft speed after a
first
stage period and to stop mixing at the end of a second stage period.
Among many methods of calculation of an increase temperature rate for the
first embodiment, one preferred method is to detect and store a sensed
temperature
of the mixing batch from 30 to 0.5 ms and to calculate an average of each
preceding
5 to 10 recorded batch temperature values. Trigger setpoints of from 1.5 to 0
degrees per second are preferred for the first embodiment, where a maximum
temperature increase rate is not being used to determine the trigger setpoint.
For a trigger setpoint for the second embodiment, an absolute value of from
to 0 percent crystallinity is preferred, more preferred is from 2-0 percent
detected
crystallinity of the pharmaceutical or drug being measured. A trigger setpoint
for a
rate of crystallinity decrease is preferably from 20 percent per second to 0
percent
per second.
15 For the first embodiment, a stop point for thermokinetic mixing for a
specific
component combination is determined by trial, where acceptable low or non-
existent
levels of crystallinity are found and degradation of the drug or
pharmaceutical is
within acceptable limits. For the second embodiment, a stop point for
thermokinetic
mixing for a specific component combination is determined by trial, where
20 acceptable low or non-existent levels of crystallinity are found and
degradation of the
drug or pharmaceutical is within acceptable limits or by a pre-determined low
level of
detected crystallinity.
FIG. 25 shows an analysis graph of a single shaft speed batch showing
sensed temperature in degrees F and shaft rotational speeding in RPMs against
process time, where the process is stopped at a detected temperature plateau
(shown in a sloped, broken line) at about 15.3 seconds. In the process of FIG.
25,
the batch contains these components: ltraconazole; Eudragit L100-55 (1:2
ratio).
The graph grid blocks define a positive slope of 25 degrees F per second from
opposing corners. Plateau detection occurs in this specific example preferably
at a
slope of at about 15 degrees F per second or less, or, more preferably at
about 10
degrees F per second or less. The process of FIG. 25 shows actual results of
thermokinetic mixing at a single low shaft speed (about 1900 RPM) terminated
at
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detection of a temperature plateau by the mixer control program
microprocessor.
Some component combinations may achieve adequate reduction in crystallinity at
the plateau detection step, as in this case. This embodiment of the invention
is
referred to herein as the single low shaft speed batch embodiment.
FIG. 26 Analysis graph of a single shaft speed batch showing sensed
temperature in degrees F and shaft rotational speeding in RPMs against process
time, where the process is stopped after a detected temperature plateau at
about
15.8 seconds (shown in a sloped, broken line) at a second period time at about
20.8
seconds, or a detected reduction in crystallinity (if a crystallinity probe is
used). In
the process of FIG. 26, the batch contains these components: Itraconazole;
Eudragit
L100-55 (1:2 ratio).. The graph grid blocks define a positive slope of 10
degrees F
per second from opposing corners. Plateau detection occurs in this specific
example
preferably at a slope of at about 20 degrees F per second or less, or, more
preferably at about 10 degrees F per second or less. The process of FIG. 26
shows
actual results of thermokinetic mixing at a single low shaft speed (about 1600
RPM)
terminated (Process Stop ¨ means either removal of the batch from the mixing
chamber or other effective stop of thermokinetic mixing) at detection of
passage of a
time period after temperature plateau detection by the mixer control program
microprocessor. Some component combinations may achieve adequate reduction in
.. crystallinity at a time period after the plateau detection step, as in this
case. In this
case, the additional time period after plateau detection is about 5 seconds.
This
embodiment of the invention is referred to herein as the single low shaft
speed plus
additional time batch embodiment.
FIG. 27 Analysis graph of a two shaft speed batch showing sensed
temperature in degrees F and shaft rotational speeding in RPMs against process
time, where the shaft speed is increased at a detected temperature plateau at
about
9.5 seconds and the process is stopped at detected temperature, second speed
time (about 12.7 seconds), or a detected reduction in crystallinity (if a
crystallinity
probe is used). In the process of FIG. 27, the batch contains these
components:
Griseofulvin; Povidone K30 (1:3 ratio). The graph grid blocks define a
positive slope
of 25 degrees F per second from opposing corners. Plateau detection occurs in
this
specific example preferably at a slope of at about 10 degrees F per second or
less,
or, more preferably at about 5 degrees F per second or less. The process of
FIG. 27
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shows actual results of thermokinetic mixing at a first low shaft speed (about
1500
RPM), increasing shaft speed to about 2250 RPM, and stopping the thermokinetic
mixing at about 12.5 seconds. Many component combinations may achieve
adequate reduction in crystallinity at a time period at a higher shaft speed
after the
plateau detection step, as in this case. In this case, the additional time
period after
plateau detection is about 3.2 seconds. This embodiment of the invention is
referred
to herein as the low shaft speed to high shaft speed batch embodiment. In
comparing the processes of FIG. 27 to that of FIG. 26, the process of FIG. 27
achieves a desired reduction in crystallinity for a process stop at about a
reduction in
total process time by 30 to 40 percent.
All of the compositions and/or methods disclosed and claimed herein can be
made and executed without undue experimentation in light of the present
disclosure.
While the compositions and methods of this disclosure have been described in
terms of preferred embodiments, it will be apparent to those of skill in the
art that
variations may be applied to the compositions and/or methods and in the steps
or in
the sequence of steps of the method described herein without departing from
the
concept, spirit and scope of the disclosure. All such similar substitutes and
modifications apparent to those skilled in the art are deemed to be within the
spirit,
scope and concept of the disclosure as defined by the appended claims.
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