Note: Descriptions are shown in the official language in which they were submitted.
~ 2126g26
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APPARATUS FOR MIXING AND DETECTING ON-LINE HOMOGENEITY
TECHNICAL FIELD
This invention relates to an apparatus for mixing compositions of matter into a
5 homogeneous mixture and detecting on-line the homogeneity and potency of the
mixture, and a method for using the same. More particularly, this invention relates to
an apparatus for mixing the components of a pharmaceutical composition into a
homogeneous mixture and detecting on-line the homogeneity and potency of said
pharmaceutical composition.
BACKGROUND OF THE INVENTION
The mixing of pharmaceutical compositions is a crucial step in processing an
active drug into a form for administration to a recipient. Pharmaceutical compositions
usually consist of five (5) or more separate components, including the active drug,
which must be mixed into a homogeneous mixture. It is critical to determine the
concentration of the active drug in a pharmaceutical mixture. It is also advantageous
to determine the concentration of the other non-active components within the final
homogeneous mixture. The assurance that the pharmaceutical composition is
homogeneous is necessary in order to ensure the appropriate dosage of the activedrug is delivered to a recipient.
The concentration of the non-active components in a pharmaceutical mixture is
also important because it determines the physical properties of the mixture. Forexample, the non-active components of pharmaceutical compositions are known as
excipients. An example of an excipient is a disi"~egrant. Disintegrants determine the
rate of dissolution of a tablet in a recipient's stomach. Therefore, if the disintegrant is
not homogeneously distributed in the pharmaceutical mixture, then the resulting tablets
may not dissolve at a uniform rate. This could give rise to quality, dosing and
bioavailability problems.
Typically, homogeneity of a pharmaceutical composition referred to the
distribution of the active drug in the pharmaceutical composition. Potency of a
pharmaceutical composition referred to the amount of the active component in a
pharmaceutical co",posit;on. Traditionally, the determination of the potency andhomogeneity of a pharmaceutical mixture has been time consuming. In addition,
traditional methods measure the potency and homogeneity of only the active
21~5~26
component in a pharmaceutical composition and gives no information conceming thehomogeneity of the non-active components.
The traditional methods typically involve using a conventional blender such as
a core blender, a ribbon blender, a ~ -blender or the like, to mix the components of
a pharmaceutical composition. When the mixture is thought to be finished, the blender
is stopped and usually nine or more samples of the mixture are removed from various
locations in the conventional blender. The blender remains shut down while the
samples are taken to a laboratory and analyzed for potency. The samples are typically
analyzed using High Performance Liquid Chromatography (HPLC). The HPLC analysis
determines the concentration of only the active component in each of the samples.
The measurements determine whether the active component is uniformly dispersed or
homogeneous in the mixture and present at an appropriate concentration level. This
information reflects the potency of the mixture and if the potency of each of the
samples is the same, then the mixture is considered to be homogeneous. HPLC
analysis does not establish the concentration of the non-active components of the
mixture. Homogeneity of all the components of a pharmaceutical mixture is important
because the dispersion of certain components will ultimately affect the physicalproperties of the final form of the pharmaceutical composition, as discussed
hereinabove. The traditional analysis can take from 24 to 48 hours to complete.
Another time consuming aspect of the traditional method is the hit or miss
approach to determine when the mixture is homogeneous. Typically, the blender is run
for a predetermined amount of time. The blender is stopped and the samples are taken
to be tested. If the mixture is not homogeneous then the blender is run again and the
testing procedure is repeated. Further, the mixture may reach homogeneity at a time-
point before the predetermined set time for blending. In the first case more testing is
carried out than is required, and in the second case valuable time is wasted in blending
beyond the end-point. It is also possible that over blending can cause segregation of
the components. Therefore, the time that is wasted in both cases and the possible risk
of segregation due to over blending can be avoided by an apparatus which could
detect on-line the potency and homogeneity of the pharmaceutical mixture. The term
on-line means that the blender does not have to be turned off in order to take the
measurements to determine homogeneity and potency.
For the foregoing reasons, there has been a long felt need in the art for an
apparatus which can blend the components of a pharmaceutical mixture and detect on-
fi
line the potency and homogeneity of all the components of a
pharmaceutical mixture. There is currently no apparatus in
the art which can blend a pharmaceutical composition and
detect on-line the homogeneity and potency of a pharmaceutical
mixture.
SUMMARY OF THE INVENTION
This invention provides an apparatus for mixing
compositions of matter into a homogenous mixture and detecting
on-line the homogeneity of said mixture, which comprises: (a)
mixing means for mixing said compositions of matter; and (b)
spectroscopic detection means for detecting on-line the
homogeneity of said mixture.
The mixing means has a container for holding the
compositions of matter to be mixed, preferably, said container
rotates about an axis of rotation during the mixing process.
The container has an aperture covered and sealed by a pellucid
sealing means. In close proximity to, preferably abutting,
the pellucid sealing means is a detection means for detecting
the on-line spectroscopic characteristics of the mixture of
compositions of matter.
In a preferred embodiment of this invention, said
aperture is sealed by an arbor (a hollow shaft). A detection
means for detecting the on-line spectroscopic characteristics
of the mixture of compositions of matter is rotatably mounted
through said arbor. A means for detecting the rotational
position of said container is attached to the mixing means.
The means for detecting rotational position relays to a data
acquisition and control computer the rotational or angular
position of said container. The data acquisition and control
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; 72222-237
computer synchronizes the taking of spectroscopic data, by the
detection means with a predetermined single rotational
position or multiple rotational positions of said container of
the mixing means. The taking of spectral data at a consistent
predetermined point in the rotation of the container assures a
greater degree of accuracy in determining the homogeneity of
the mixture being mixed.
Another aspect of this invention is directed to a
method for mixing compositions of matter into a homogeneous
mixture and simultaneously detecting on-line the homogeneity
and potency of the mixture of compositions of matter. The
method comprises the steps of charging the mixing means with
the individual compositions of matter to be mixed; mixing the
compositions of matter; simultaneously detecting on-line the
spectroscopic characteristic of the mixture with a detection
means; optionally, synchronizing the detecting on-line of the
spectroscopic characteristic of the mixture by a detection
means with a predetermined single or multiple rotational
position of a container which rotates about an axis of
rotation, of a mixing means; and either
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manually shutting off the appar~ s of this invention or automatically shutting off the
apparatus of this invention utilizing a data ~cq~ ~isition and control computer when the
spectroscopic characteristics of said mixture reach a predete~ i"ed homogeneity and
potency end point as compared to a spectra of a known homogeneous mixture or until
5 the variance in the spectroscopic characteristic converge.
This invention, therefore, allows spectra of a mixture to be coilected while themixing means is in motion, thereby, avoiding the down-time and over-shooting or
under-shooting the end point which is characteristic of the traditional process for mixing
and determining the potency of a mixture.
Other features and advantages of this invention will be apparent from the
specification and claims and from the accompanying drawings which illustrate certain
embodiments of this invention.
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 illustrates a side view of an exemplary apparatus of this invention, witha cross sectional view of the container 101 and first axle 125.
FIG. 2 illustrates a top view of the apparatus depicted in FIG. 1.
FIG. 3 illustrates an enlarged view of FIG. 1, broken away to illustrate a portion
of the container and its attachment to the spectroscopic means.
FIG. 4 illustrates a side view of a transflectance probe attached to an axle.
FIG. 5 illustrates a representational side view of a conventional blender which
has internal mixing means (e.g., ribbon blender or a core blender).
FIGS. 6a to 6d are cross sectional views taken along line 5a showing the
blender aperture and illustrate different means of connecting the detection means to the
blender apparatus.
FIG. 7 illustrates an enlarged cross sectional view of an embodiment of the
container, arbor and the various inserts within the arbor.
FIG. 8 illustrates another embodiment of the apparatus of this invention having
a means for detecting rotational position of the container.
DETAILED DESCRIPTION OF THE INVENTION
Different types of blenders are currently used in the art for mixing pharmaceutical
compositions. One type of blender is exemplified by the ~\/a-blender which mixescompositions of matter, such as powders or liquids by ru~ali"g the container which
holds the compositions of matter about an axis of rotation. Therefore, one of the
embodiments of this invention is a modified '~"-blender, which is illustrated in FIG. 1.
~126826
According to FIG.1 and FIG. 2 container 101 holds the compositions of matter
to be mixed. Container 101 has a general ~\/" shape which is formed from a first hollow
leg 201 open to a second hollow leg 204 which converge with each other at an angle,
thereby giving it the ll\/a shape. Container 101 has an outward facing surface wall 104,
5 which is the outside surface of the longer portion of legs 201 and 204 of container 101.
Aperture 107 is disposed through outward facing surface wall 104. The aperture
position is fixed by the position of second axle 111 ar~d said second axle's connection
with second hollow leg 204, which is described hereinbelow.
Openings 115 at the top of container 101 are used for either charging container
10 101 with the individual compositions of matter which are to be mixed or discharging the
finished homogeneous mixture. Openings 115 are covered and sealed during the
mixing process by top covers 207. Top covers 207 are secured to container 101 bytop clasps 208. Opening 119 at the bottom of container 101 is used for either charging
container 101 with the individual compositions of matter which are to be mixed or
15 discharging the finished homogeneous mixture. Opening 119 is covered and sealed
during the mixing process by bottom cover 122. Bottom cover 122 is secured to
container 101 by bottom clasps 123.
First ballbearing pillow block 210 has a lateral hole through it, preferably at its
center. Ballbearing pillow blocks are well known in the art; they have bearings in them
20 which allow for free rotation of an axle which is disposed in the hole and they also
function as supports. These features of the ballbearing pillow block are more fully
explained below. First support 128 has a lateral hole through it, disposed at its top
end. First ballbearing pillow block 210 is disposed between container 101 and first
support 128 and is attached, usually by bolts, to the side of first support 128 so that
25 the hole of first ballbearing pillow block 210 and the hole of first support 128 are
aligned.
Second ballbearing pillow block 213 has a lateral hole through it, preferably atits center. Second support 131 has a lateral hole through it disposed at its top end.
Second ballbearing pillow block 213 is disposed between container 101 and second30 support 131 and is attached, usually by bolts, to the side of second support 131 so
that the hole of second ballbearing pillow block 213 and the hole of second support
131 are aligned.
Second axle 111 has a first end and a second end, it is attached by its first end
to container 101. The second end of second axle 111 is rotatably mounted through
2126~26
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-6-
the aligned lateral holes of second ballbearing pillow block 213 and second support
131 and connected to a means for rotation 216, such as a motor. The motor can beconnected directly to second axle 111 or it can be connected by a drive mechanism
219, such as a chain or a belt. Motor 216 rotates container 101 thereby mixing the
5 individual compositions of matter into a homogeneous mixture.
According to FIG. 3, first axle 125 has a first end and a second end. First axle125 is attached by its first end through aperture 107 to container 101 in such a manner
so that a portion of the first end of first axle 125 protrudes into container 101. A portion
of the first end of first axle 125 has to protrude into container 101 enough so that the
10 compositions of matter which are being mixed come into contact with the portion of the
first end of first axle 125 during the mixing process. The second end of first axle 125
is rotatably mounted through the aligned lateral holes of first ballbearing pillow block
210 and first support 128 so that first axle 125 is aligned with second axle 111 to form
a level and horizontal axis of rotation. The horizontal axis of rotation must be high
15 enough up the legs of container 101 so that container 101 can freely rotate 360~ about
the axis of rotation formed by said first and second axles.
As shown in FIG. 1, first axle 125 has a bore 134 therethrough. Bore 134 is
covered at the first end of first axle 125 by a pellucid sealing means 137, such as a
pellucid window or a transflectance probe. Said pellucid window can be made from20 glass, quartz or sapphire, depending upon the wavelength region of the radiation
issuing from the spectroscopic means which is discussed hereinbelow. In the present
embodiment a pellucid window is preferred as the pellucid sealing means and quartz
is the preferred material for pellucid window 137.
Alternatively, bore 134 is covered at the first end of first axle 125 by
25 transflectance probe 400, shown in FIG. 4. According to FIG. 4 transflectance probe
400 is comprised of housing 405, pellucid lens 410, reflector 415 and has a void 420.
Examples of conduction means for conducting radiation 140, are light pipes,
optics and a fiber optic bundle. The fiber optic bundle is the preferred conduction
means for this embodiment. According to FIGS.1 and 3, fiber optic bundle 140 has30 a first end and a second end. The first end of the fiber optic bundle 140 runs through
and is covered by sleeve 141. Sleeve 141 housing fiber optic bundle 140 is removably
disposed inside bore 134 so that the first end of fiber optic bundle 140 is in close
proximity to pellucid window 137 so that the radiation emanating from said fiber optic
bundle passes through pellucid window 137 at an essentially horizontal level and
'~ ~125826
-7-
without distortion from outside sources of i"le,~erence which may disrupt the source
radiation. Pl~ferably said fiber optic bundle abuts said pellucid window. The second
end of fiber optic bundle 140 is removably attached to spectroscopic means 143
through opening 147 in spe-.tloscopic means 143. Opening 147 is where the radiation
5 from spectroscopic means 143 emanates and the diffusely reflected radiation orreflected radiation from the mixture via fiber optic bundle 140 is admitted . The following
are examples of p~fer-ed spectroscopic means: infrared spectrophotometer; ultraviolet-
visible spectrophotometer; near infrared spectrophotometer; mid-range infrared spectro-
photometer and raman spectrophotometer.
Fiber optic bundle 140 contains two sets of optical fibers. The first set of optical
fibers convey radiation emanating from spectroscopic means 143 to the mixture inside
container 101. Pellucid window 137 allows the radiation emanating from fiber optic
bundle 140 to pass through to the mixture without distortion.
If the mixture is a solid then the radiation signal is analyzed by reflectance. The
15 radiation hitting the solid mixture is diffusely reflected. The second set of optical fibers
collect the diffusely reflected radiation from the mixture and convey it back tospectroscopic means 143.
If the mixture is a liquid then the radiation is analyzed by transflectance. For a
liquid mixture transflectance probe 400 is fitted onto the first end of axle 125 in place
20 of pellucid window 137. The radiation emitting from the first set of fibers of fiber optic
bundle 140 passes through pellucid lens 410 and through the liquid mixture that is in
void 420 between reflector 415 and housing 405. Pellucid lens 410 is made out of the
same types of material as enumerated for pellucid window 137 and serves the samefunction as pellucid window 137. The liquid mixture distorts the radiation, the distorted
25 radiation is then reflected back by reflector 415 to fiber optic bundle 140 where the
second set of optical fibers collect the reflected radiation and convey it to spectroscopic
means 143.
Spectroscopic means 143 stores and analyzes the diffusely reflected or ~eflectedradiation; or spectroscopic means 143 can further transmit the spectral data to a
30 computer which then analyzes it.
The particularly pr~ferled spectroscopic means is the NlRSystems model 6500
spectrophotometer (anearinfrared spectrophotometer) availablefrom NlRSystems Inc.
12101 Tech Road Silver Spring MD 20904. The computer which analyzes the data
can be any personal computer such as the Zeos 33 MHz 80846DX PC with 8 Mb of
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RAM. The data is collected in the computer using Near infrared Spectral AnalysisSoftware (NSAS), which is the instrument control package provided with the
spectroscopic instrument from NlRSystems. The data is then analyzed in Matlab
(software package) available from The Mathworks Inc. (The Mathworks Inc., Cochituate
5 Place, 24 Prime Park Way, Natick, MA, 01760).
FIG. 5 is a generic representation of another type of conventional blender used
for mixing compositions of matter. This other type of conventional blender does not
require the blender's container to be rotated about an axis of rotation to mix the
individual compositions of matter into a homogeneous mixture. Instead, this other type
10 of conventional blender relies upon agitators inside the container, such as blades or
stirrers, to mix the compositions of matter into a homogeneous mixture. A ribbonblender is an example of a conventional blender which utilizes blades. A core blender
is an example of a conventional blender which utilizes stirrers. In addition to mixing
powders and liquids these blenders can also mix compositions of matter for salves and
15 creams.
According to FIG. 5, the rectangular box designated by 500 represents any
stationary conventional blender which relies upon internal agitators to mix compositions
of matter into a homogeneous mixture. Blender 500 has an aperture 502 in one of the
blender's walls 501. However, more than one aperture can be present in any one or
20 more of the blender's walls. The aperture must open into the inside of the container
portion of blender 500 so that the detection means will be able to convey the radiation
from the spectroscopic means to the mixture inside the container of the blender and
the reflected or transflected radiation can be collected and analyzed.
FIG. 6a illustrates an embodiment of aperture 502, blender wall 501 and
25 conduction means 140 wherein blender wall 501 is dimpled inward into the container
of blender 500. Aperture 502 in blender wall 501 is covered and sealed by pellucid
barrier 503. Pellucid barrier 503 is made out of the same types of material as
enumerated for pellucid window 137 and serves the same function as pellucid window
137. The first end of conduction means 140 is in close proximity to, preferably
30 abutting, pellucid barrier 503 and the second end of means for conducting radiation
140 is removably attached to spectroscopic means 143 as illustrated in FIG. 1 and
discussed hereinabove.
FIG. 6b illustrates another embodiment of aperture 502, blender wall 501 and
conduction means 140. Aperture 502 is covered and sealed by attaching conduction
21~6~2~
g
means 140 to blender wall 501 through aperture 502. Conduction means 140 protrudes
into the container of blender 500. The end of conduction means 140 protruding inside
the container is covered by pellucid barrier 503. Alternatively, transflectance probe 400,
discussed hereinabove, can be i"terchanged for pellucid barrier 503.
FIG. 6c illustrates an embodiment of aperture 502, blender wall 501 and
spectroscopic means 143. In this embodiment pellucid barrier 503 covers and seals
aperture 502 in blender wall 501. Spectroscopic means 143 is placed next to blender
wall 501 so that opening 147 in spectroscopic means 143, from which the radiation
emanates and is admitted, is in close proximity to, preferably abutting, pellucid barrier
503.
FIG. 6d illustrates a further embodiment of aperture 502, blender wall 501 and
conduction means 140. In this embodiment pellucid barrier 503 covers and seals
aperture 502 in blender wall 501. Conduction means 140 is placed so that its first end
is in close proximity to, preferably abutting, pellucid barrier 503.
FIGS.6a,6b and 6d show certain prefer,ed embodiments in which a conduction
means 140 can be combined with blender 500 in order to employ on-line acquisition
of spectral data of the mixture being mixed so that the potency and homogeneity of a
pharmaceutical mixture can be determined. The acquisition of spectra is accomplished
in the same manner as is discussed hereinabove for the exemplary embodiment
represented by the modified V-blender.
In an embodiment wherein said conduction means 140, shown in FIGS.6a,6b
and 6d is a fiber optic bundle, the fiber optic bundle 140 contains two sets of optical
fibers. The first set of optical fibers convey radiation from spectroscopic means 143 to
the mixture. Pellucid barrier 503 allows the radiation emanating from the first set of
optical fibers of fiber optic bundle 140 to pass through to the mixture of compositions
of matter without distortion. The radiation contacting the mixture is diffusely reflected
in case of solid mixture or transflected in the case of liquids. The second set of optical
fibers collect the radiation that is diffusely reflected or reflected from the mixture and
convey it back to the spectroscopic means 143. Spectroscopic means 143 analyzes
the radiation or spectroscopic means 143 can further convey the data to a computer
which will then analyze it.
FIG. 6c illustrates an embodiment of this invention which does not require a
conduction means 140, instead a spectroscopic means 143 can be placed directly next
to blender 500. The exchange of radiation from spectroscopic means 143 and the
w 2126826
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diffusely reflected radiation from the mixture passes through opening 147 without the
aid of a conduction means 140.
In a pr~er,ed embodiment, according to FIG. 7, aperture 107 is occlusively
sealed by arbor 180. Arbor 180 has a tunnel 182 ther~lhrough and said arbor has a
5 first end and a second end. Hollow pipe 151 has a first end and a second end; said
first end of hollow pipe sealed by an optically transparent sealing means 152, such as
a lens or a transflectance probe 400. A lens which is used as an optically transparent
sealing means 152 is made of the same materials as enumerated for pellucid sealing
means 137. The inside diameter of arbor 180 is larger than the outside diameter of
10 hollow pipe 151 so that said hollow pipe may be removably disposed in said arbor.
The first end of arbor 180 extends into container 101 so that it will come into contact
with the compositions of matter being mixed in the container. The second end of arbor
180 is rotatably mounted through the aligned lateral holes of first ballbearing pillow
block 210 and first support 128 so that arbor 180 is aligned with second axle 111 to
15 form a level and horizontal axis of rotation. The horizontal axis of rotation must be high
enough up the legs of container 101 so that container 101 can freely rotate 360~ about
the axis of rotation formed by arbor 180 and second axle 111 . Said fiber optic bundle
140 is disposed inside of hollow pipe 151 with said first end of said fiber optic bundle
140 abutting lens 152 or pellucid lens 410 if the first end of hollow pipe 151 is sealed
20 by transflectance probe 400. Hollow pipe 151 is removably disposed within tunnel 182
of arbor 180 with the first end of hollow pipe 151 preferentially disposed, but not
necessarily, beyond the first end of arbor 180. A self-lubricating seal 185 such as
TEFLONI (TEFLON- is a rey;;~lered trademark of E.l. DuPont de Nemours and Co.), is
occlusively disposed between the first end of hollow pipe 151 and the first end of arbor
25 180 in order to prevent leakage of the compositions of matter being mixed in container
101 into tunnel 182 of arbor 180. Seal 185 is self-lubricating and it rotates with arbor
180 and, hence, seal 180 rotates around the first end of hollow pipe 151 and, therefore,
hollow pipe 151 remains stationary.
In another preferred embodiment of this invention, according to FIG. 8, a means
30 for detecting rotational (angular) position 150 of container 101 is incorporated into the
mixing means. Some exar"~les of means for detecting rotational position are an
absolute digital shaft encoder, a pulse encoder, an optical encoder and an analog
encoder, the foregoing list is not exhaustive and is not intended to exclude any other
possible means for detecting rotational position. A brace 155 has a general "U- shape
2126~2~
-1 1 -
and has a first leg and a second leg, the first leg of brace 155 is attached to means for
detecting rotational position 150. The second leg of brace 155 is attached to second
support 131. Further, FIG. 8 shows a first connecting shaft 160a and a second
connecting shaft 160b. The first connecting shaft 160a has a first end and a second
5 end. The second connecting shaft 160b has a first end and a second end. The first
end of first connecting shaft 160a is attached horizontally and in-line to second axle
111 so that it turns with the rotation of second axle 111. The second end of first
connecting shaft 160a is flexibly and fixedly connected to coupling 165. The first end
of second connecting shaft 160b is flexibly and fixedly connected to coupling 165 so
10 that the second end of first connecting shaft 160a and the first end of second
connecting shaft 160b are facing end to end but do not touch each other. The second
end of second connecting shaft 160b is attached to the means for detecting rotational
position 150. Coupling 165 transmits the rotational force from first connecting shaft
160a to second connecting shaft 160b so that both first connecting shaft 160a and
15 second connecting shaft 160b turn simultaneously with the rotation of second axle 111.
Further, coupling 165 flexibly and fixedly holds first connecting shaft 160a and second
connecting shaft 160b in order to reduce the rotational stress, during the rotation of
second axle 111, between first connecting shaft 160a and second connecting shaft160b. The means for detecting rotational position 150 is interfaced by a first set of
20 communication wires 170 to a relay box, where said relay box is interfaced with data
acquisition and control computer 163 by a second set of communication wires. Thesecond set of communication wires relays information from the relay box to data
acquisition and control computer 163. In an embodiment wherein the means for
detecting rotational position 150 is an absolute digital encoder, the relay box i"ler~.reI~
25 the digital signal from the absolute digital encoder to an ASCII number, the ASCII
number represents the rotational position of container 101 in degrees. The ASCIInumber is transmitted to data acquisition and control computer 163 by the second set
of communication wires. Data acquisition and control computer 163 is interfaced to
spectroscopic means 143 by a third set of communication wires 173. As container 101
30 rotates, the rotation of second connecting shaft 160b is detected by the means for
detecting rotational position 150, which relays the rotational position of container 101
to the relay box through the first set of communication wires 170. The relay box then
relays the information to data acquisition and control computer 163 through the second
set of communication wires. Data acquisition and control computer 163, using a
212~826
control software such as Labview (commercially available from National Instruments,
Austin, Texas 78730), synchronizes the collection of spectroscopic data by
spectroscopic means 143 with a predetermined position of the means for detectingrotational position 150 which l.anslcltes to a rotational position of container 101, so that
5 spectroscopic data is consistently collected at the predetermined rotational position of
container 101. One or more predetermined rotational position points of container 101
may be selected to collect spectral data. The collection of spectroscopic data by
spectroscopic means 143 is executed by software programs such as Microsoft
Windows- 3.1 (commercially available at most computer supply stores) and WINSAS-
10 (commercially available from NlRSystems Inc. Silver Springs, Maryland). The WINSASprogram is instructed as to when to start collecting the spectroscopic data by a control
software program such as Labview- via Dynamic Data Exchange (DDE is a feature that
is innate to Microsoft Windows~ 3.1). Further, data acquisition and control computer
163 is interfaced by a fourth set of communication wires to said relay box. Means for
15 rotation 216 may be controlled manually or means for rotation 216 may be controlled
by said relay box. The interface of data acquisition and control computer 163 to the
relay box, allows the data acquisition and control computer 163 to turn on or off means
for rotation 216 when the data acquisition and control computer determines, by the
mathematical analysis described below, that the compositions of matter being mixed
20 has reached the homogeneous end-point. The homogeneous endpoint is determinedby transferring the spectroscopic data collected by WINSASI to another software
program such as InStep- (commercially available from Infometrix Inc., Seattle,
Washington) via DDE, the spectroscopic data is then analyzed using pre-c~cu~-tedmodels which were developed using a software program such as Pirouette-
25 (commercially available from Infometrix Inc., Seattle, Washington). Means for rotation216 may be stopped at desired time intervals before the compositions of matter being
mixed reaches a homogeneous end-point so that samples may be taken from container
101 for analysis, or means for rotation 216 may be stopped for any other reasonscontemplated by a user. The aforesaid sets of communication wires are any device30 capable of transmitting optical or electrical signals.
The data acquisition and control computer used in the present embodiment is
the Toshiba T6400DX, 33 MHz, 486DX with 16 Mb of RAM, however, the data
acquisition and control computer can be any computer with similar or more advanced
capabilities.
_ 2126~26
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The initial spectra of the mixture will be closest to the spectrum of each of the
individual components of the mixture. As the mixing apparatus begins to mix the
compositions of matter, the spectra of the mixture will appear less like the spectra of
the individual components and more akin to the spectra of a homogeneous mixture.5 Eventual~y the spectra will converge to that of a homogeneous mixture. Utilizing this
analytical method the distribution of each of the components in the mixture, the active
component as well as the inactive components, can be measured. Thus, enabling the
apparatus of this invention to determine the total overall homogeneity of the mixture.
Calculations are performed to estimate when all components of the mixture are
10 homogeneous by measuring the change in a group of spectra as a function of time.
For example, a group of 50 spectra are taken at one minute intervals. The standard
deviation of the wavelengths of spectra 1-5, followed by 2-6, and 3-7 ... etc. are
calculated. The resulting standard deviation spectra shows which regions of the
spectra were changing the most. Calcu~ting the variance in each of the individual
15 deviation spectra would then give a measure of the total variance of the mixture as a
function of time. When the total variance has diminished to a constant, the blend is
considered homogeneous. Alternatively, a computer can be programmed with a
spectrum of a known homogeneous mixture. The mixing is complete when the
spectrum of an in-progress mixture matches the spectrum of the known homogeneous20 mixture.
The embodiments of this invention, which are illustrated in FIGS. 1 to 4 and
FIGS. 5, 6a to 6d, 7 and 8, allow spectra of a mixture of compositions of matter to be
collected while the blender is in motion. Therefore, the apparatus of this invention
avoids the down-time that is the principal drawback of the traditional process. The
25 apparatus of this invention allows the detection on-line of the homogeneity and potency
of the mixture, a feature which is not available in the traditional apparatuses.The apparatus of this invention can be further modified to accommodate more
than one detection means wherein said detection means is a spectroscopic means
optionally fitted with a conduction means as described hereinabove. The apparatus of
30 this invention with multiple spectroscopic means can be connected with the same type
of spectroscopic means or with dfflerent types of spectroscopic means. The exemplary
apparatus of this invention, a modified ~V"-blender, can be further modified to
accommodate two spectroscopic means by using a hollow second axle. A conduction
means can be disposed within said hollow second axle in the same manner as
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-14-
described for said fiber optic bundle in said bore of said first axle, describedhereinabove.
A conventional blender of the type 500 can be further modified to accommodate
multiple spectroscopic means by making as many apertures as required in any desired
5 locations in the blender's walls. Each of the multiple apertures could then be fitted with
a conduction means which would be connected to a spectroscopic means as illustrated
in FIGS. 6a, 6b and 6d and described hereinabove; or each aperture could be abutted
by a spectroscopic means as illustrated in FIG. 6c and described hereinabove; or a
combination of the embodiments illustrated in FIGS. 6a to 6d.
An advantage of using more than one detection means of the same type with
an apparatus of this invention is that it would allow for acquisition of spectral
characteristics of the mixture from two or more locations of the apparatus of this
invention. This embodiment of the invention would further insure that the mixture was
homogeneous throughout the container.
An advantage of using different types of detection means with an apparatus of
this invention is illustrated in the following circumstance. In a pharmaceuticalcomposition there are various components as described hereinabove. Some of the
components may only be detectable by one type of radiation, such as near-infrared
radiation. The other components of said pharmaceutical composition may only be
detectable by another type of radiation other than infrared, for example visible radiation.
In such a situation it would be advantageous to have two spectroscopic means
connected to the mixing means. The first spectroscopic means, a near-infrared
spectrophotometer, and the second spectroscopic means, avisible spectrophotometer.
Each spectrophotometer would then detect the spectroscopic characteristics of the
components of the pharmaceutical composition which it can detect.
The apparatus of this invention can also be fitted with an alarm which would
signal the operator of the apparatus of this invention when the mixture had reached the
homogeneity and potency end point. Alternatively, the system could be automatically
triggered to shut off when the mixture reaches the homogeneity and potency end point.
It should be understood that the invention is not limited to the particular
embodiments shown and described herein, but that various changes and modi~ica~ions
may be made without departing from the spirit and scope of this novel concept asdefined by the following claims.
