JPH0768146A - Apparatus and method for mixing and detecting mixture - Google Patents

Abstract

PURPOSE: To eliminate danger of separation by a uselessly consumed time and excessive blending by mixing a mixture to a homogeneous mixture and detecting on-line the spectroscopic characteristic based the homogeneity and effectiveness of the mixture. CONSTITUTION: A vessel 101 rotating about the axis of rotation has a hole 134 covered and sealed by a transparent window 137 and is provided with a detecting means for detecting on-line the spectroscopic characteristic of the mixture in opposition contact therewith. Namely, a sleeve 141 housing a fiber optical bundle 140 as a transmission means for transmitting radiation is arranged removably to the inner side of the hole 134 and the end of the fiber optical bundle 140 is in opposition contact with the transparent window 137. The second end of the fiber optical bundle 140 is removably mounted to a spectroscope 143 via the opening 147 of the spectroscope 143. The radiation from the spectroscope 143 diverges in the opening 174 so that the radiation dispersed and reflected from the mixture via the fiber optical bundle 140 enters the opening.

Description

Detailed Description of the Invention

[0001]

This invention relates to a mixture of substances (comp
and a method of using the same for the on-line detection of the homogeneity and effectiveness of the mixture. More particularly, the present invention relates to an apparatus for mixing the components of a drug mixture into a homogeneous mixture and detecting the homogeneity and effectiveness of the drug mixture on-line.

[0002]

2. Description of the Related Art The mixing of drug mixtures is due to the form of administration to the recipient and the active drug.
ug) is a difficult process. Drug mixtures usually consist of five or more independent components, including the active drug, which must be mixed into a homogeneous mixture. It is important to determine the concentration of active drug in the drug mixture. Furthermore,
It is also important to determine the concentration of other inactive components in the final homogeneous mixture. Ensuring that the drug mixture is homogeneous is necessary to ensure that the appropriate formulation of the active drug is delivered to the recipient.

The concentration of inactive ingredients within the drug mixture is also important for determining the physical properties of the mixture. For example, the inactive components of a drug mixture are known as excipients. Disintegrants determine the rate at which the tablet dissolves in the recipient's stomach. Therefore, if the disintegrant is not homogeneously dispensed within the drug mixture, the tablets cannot dissolve at a uniform rate. This will cause problems of quality, dose and bioavailability.

In general, the homogeneity of drug mixtures has been mentioned with regard to the distribution of the active drug within the drug mixture. The effectiveness of the drug mixture was referred to as the amount of active ingredient in the drug mixture. Heretofore, determining the efficacy and homogeneity of drug mixtures has been time consuming. In addition, the previous methods measure the efficacy and homogeneity of only the active ingredients within the drug mixture, and do not provide information on the homogeneity of the non-active ingredients.

[0005] Previous methods generally have used core blenders to mix the components of the drug mixture.
ender, ribbon blender
nder), V-type blender (“V” -blender)
Known blenders such as If mixing appears to be complete, the blender is stopped and typically nine or more blend samples are removed from various locations within the known blender. Samples are brought to the lab with the blender shut down for efficacy analysis. Samples are usually high performance liquid chromatography (HPLC)
Is analyzed using. This HPLC analysis determines the concentration of only active components in each sample. This measurement is
It has been determined whether the active ingredients are evenly dispersed or homogeneous within the mixture and whether they are providing suitable concentration levels. This information reflects the effectiveness of the mixture, and if the effectiveness of each sample is the same, the mixture is considered homogeneous. HPLC analysis does not mention the concentration of inactive components of the mixture. The homogeneity of all components of the drug mixture is important because the dispersion of one component ultimately affects the physical properties of the final form of the drug mixture as described above. The previous analysis took 24-48 hours to complete.

Another time consuming aspect of the previous method is the time to determine when the mixture is homogeneous. Normally, the blender runs for a predetermined amount of time. The blender is stopped and the sample is removed for testing. If the mixture is not in a homogeneous state, the blender is restarted and the test process is repeated. Furthermore, the mixture may reach a homogenous state before a preset time for blending. In the first case more test time is used than required. In the second case, useful time is wasted for blending beyond the end point. In addition, overblending can lead to component separation. for that reason,
The time wasted in these cases and the risk of separation due to overblending is eliminated by the invention that can detect the effectiveness and homogeneity of the drug mixture online. Online here means that the blender does not have to be stopped to make measurements to determine homogeneity and effectiveness.

[0007]

For these reasons, the advent of devices that can mix the components of a drug mixture and that can detect online the effectiveness and homogeneity of all components of the drug mixture. It has long been awaited. Until now, there was no device capable of mixing drug mixtures and detecting the homogeneity and effectiveness of drug mixtures on-line.

[0008]

SUMMARY OF THE INVENTION The present invention provides an apparatus that can mix a mixture of materials into a homogeneous mixture and detect the homogeneity and effectiveness of the mixture online during the mixing process. The device comprises mixing means for mixing the mixture of substances. The mixing means comprises a container for holding a mixture of substances to be mixed, preferably this container rotates about a rotation axis during the mixing process.
The container has a hole covered and sealed by a transparent sealing means. Adjacent to, preferably in contact with, the transparent sealing means, sensing means are provided for on-line sensing of the spectroscopic properties of the mixture of substances.

In a preferred embodiment of the present invention, the hole is sealed by a shaft (hollow shaft). Sensing means for on-line sensing the spectroscopic properties of the mixture of mixtures of substances are rotatably mounted via the shaft. Means for detecting the rotational position of the container are attached to the mixing means. A means for detecting the rotational position relays the rotational or angular position of the container to a data acquisition and control computer. The data acquisition and control computer is synchronized with the acquisition of spectroscopic data by means of the sensing means with a predetermined single rotational position or multiple rotational positions of the container of the mixing means. The acquisition of spectral data at consistent, predetermined points in the rotation of the vessel ensures tremendous accuracy in determining the homogeneity of the admixed mixture.

The invention further provides a method of mixing a mixture of substances into a homogeneous mixture and simultaneously detecting the homogeneity and effectiveness of the mixture of substance mixtures on-line at the same time. This method consists of filling each mixture of substances to be mixed into the mixing means, mixing the mixture of substances, at the same time detecting the spectroscopic properties of the mixture online by means of the detection means, mixing if necessary. Synchronizing on-line detection of the spectroscopic properties of the mixture by means of detection at a given single or multiple rotational positions of the container rotating about the axis of rotation of the means, to a known homogeneous mixture spectrum. By comparison, the device of the invention is manually operated by a data acquisition and control computer when the spectroscopic properties of the mixture reach the end point of the given homogeneity and effectiveness or until the fluctuations of its spectroscopic properties converge. Or, it is automatically stopped.

The present invention thus allows the collection of the spectra of the mixture during operation of the mixing means, which is a feature of previous methods of mixing the mixture and determining its effectiveness. It prevents problems such as insufficient mixing.

Other features and advantages of the invention will be apparent from the specification and claims, and also from the accompanying drawings, which illustrate certain embodiments of the invention.

[0013]

EXAMPLES Various types of blenders are currently used in the technique of mixing drug ingredients. One type of blender is a V-shaped blender. This blender mixes components such as powder or liquid by rotating a container holding a desired component around a rotation axis. Thus, one of the embodiments of the present invention is an improved V-blender as shown in FIG.

According to FIGS. 1 and 2, the container 101 holds the components to be mixed. This container 1
01 has a substantially V-shape, and the first hollow leg portion 201
And a second hollow leg 204 that opens into the first hollow leg 201, which hollow legs converge at an angle to each other, thus providing a V-shape. Container 10
1 has an outwardly facing surface wall 104, which forms the outer surface of the longer part of the legs 201, 204 of the container 101. A hole 107 is provided through the outwardly facing surface wall 104. This hole 10
The position of 7 is fixed by the position of the second shaft 111. The connection between the second shaft 111 and the second hollow leg portion 204 will be described later.

The opening 115 at the top of the container 101 is used for charging the components to be mixed into the container and for discharging the homogeneous mixture after mixing. These openings 115 are covered and sealed by a top cover 207 throughout the mixing process. These top covers 207 are fixed to the container 101 by top clasps 208. The opening 119 in the bottom part of the container 101 is used for charging the components to be mixed into the container and for discharging the homogeneous mixture after mixing. This opening 119
Are covered and sealed by a bottom cover 122 throughout the mixing process. The bottom cover 122 is fixed to the container 101 by a bottom stopper 123.

First ball bearing pillow block 2
10 preferably has a through hole in its central portion.
The ball bearing pillow block 210 is well known and has bearings therein, and these bearings allow free rotation of a shaft arranged in the through hole. Has a function as a support. These features of the ball bearing pillow block are described in further detail below. The first support 128 has a through hole at its upper end. This first ball bearing pillow block 2
10 is located between the container 101 and the first support 128, and is usually attached to the side of the first support 128 by bolts, with the holes of the first ball bearing pillow block 210. The holes of the first support 128 are aligned with each other.

Second ball bearing pillow block 2
13 preferably has a through hole in its central portion.
The second support 131 has a through hole at its upper end. This second ball bearing pillow block 213
Is arranged between the container 101 and the second support 131 and is usually attached to the side of the second support 131 by bolts, and the holes of the second ball bearing pillow block 213 and 2 It is aligned with the hole of the support 131.

The second shaft 111 has a first end and a second end, and the first end is attached to the container 101. The second end of the second shaft 111 is rotatably mounted through a matching hole between the second ball bearing pillow block 213 and the second support 131, and is connected to a rotating means 216 such as a motor. There is. This motor has a second shaft 11
It can be connected directly to the unit 1, or by a drive mechanism 219 such as a chain or belt. Motor 21
6 rotates the container 101, thus mixing the individual components into a homogeneous mixture.

According to FIG. 3, the first shaft 125 has a first end and a second end. The first end of the first shaft 125 has a hole 1
Is attached to the container 101 via the first shaft 1
A part of the first end of 25 goes into the container 101.
A portion of the first end of the first shaft 125 must be sufficiently recessed into the container 101 so that the components to be mixed can contact the portion of the first end of the first shaft 125 during the mixing process. I won't. The second end of the first shaft 125 is rotatably received in the alignment holes of the first ball bearing pillow block 210 and the first support 128, thus the first shaft 125 is aligned with the second shaft 111 and has a flat horizontal surface. It forms the axis of rotation. This horizontal axis of rotation must be located at a sufficiently high part of the leg of the container 101, so that the container 101 is at an angle of 360 ° around the axis of rotation formed by said first and second axes. It can rotate freely.

As shown in FIG. 1, the first shaft 125 has a hole 134 therethrough. This hole 134 is the first
The end of the shaft 125 is covered by a transparent sealing means 137 such as a transparent window or a transflance probe.
This transparent window may be made of glass, quartz, sapphire, or the like, depending on the wavelength range of the radiation generated by the spectroscopic means described later. In this embodiment, the transparent window is preferably a transparent sealing means and quartz is a transparent window 137.
Is preferred as the material.

On the other hand, the hole 134 has the first shaft 125 of the first shaft 125.
As shown in Fig. 4, the end of the transflance probe 4
Covered by 00. According to FIG. 4, this transflective probe 400 has a housing 405,
It is composed of a transparent lens 410 and a reflecting mirror 415, and has a space 420.

Conducting means for conducting radiation (conduc)
Examples of traction means 140 include lightweight pipes, optical and fiber optic bundles. This fiber optic bundle is the preferred conducting means for this embodiment. Figure 1
And 3, the fiber optic bundle 140 has a first end and a second end. The first end of the fiber optic bundle 140 passes through and is covered by the sleeve 141. A sleeve 141 containing the fiber optic bundle 140 is removably disposed inside the hole 134, with the first end of the fiber optic bundle 140 adjacent the transparent window 137. Thus, the fiber optic bundle 14
Radiation emanating from 0 passes through the transparent window 137, essentially at a horizontal level, without distortion from outside the source of obstacles that may block the source radiation. This fiber optic bundle 140 preferably abuts the transparent window. The second end of the fiber optic bundle 140 passes through the opening 147 of the spectroscope 143, and
It is detachably attached to 3. Radiation from the spectroscope 143 diverges at the aperture 147 and the fiber optic bundle 14
Dispersed and reflected radiation or reflected radiation from the mixture through 0 is intended to enter. Preferred spectrographs include infrared spectrophotometers, ultraviolet visible spectrophotometers, near infrared spectrophotometers, mid-range (mi)
d-range) infrared spectrophotometer, Raman (ram)
an) There are spectrophotometers and the like.

The fiber optic bundle 140 has two sets of optical fibers. The first set of optical fibers is spectroscope 14
The radiation emanating from 3 is carried to the container 101 containing the mixture. The transparent window 137 allows the radiation diverging from the fiber optic bundle 140 to pass through the mixture without distortion.

If the mixture is a solid, the radiation signal is analyzed by reflection. Radiation that strikes the solid mixture is reflected in a dispersed state. The second set of optical fibers collects the radiation reflected dispersively from the mixture and returns it to the spectrometer 143.

On the other hand, if the mixture is a liquid, the radiation is analyzed by transreflectance. In the case of a liquid mixture, the transflance probe 400 is attached to the first end of the shaft 125 instead of the transparent window 137. Radiation emanating from the first set of fibers of the fiber optic bundle 140 passes through the transparent lens 410 and through the liquid mixture in the space 420 between the reflector 415 and the housing 405. The transparent lens 410 is formed of the same type of material as the material of the transparent window 137, and provides the same function as the transparent window 137. This liquid mixture distorts the radiation which is then returned by the mirror 415 back to the fiber optic bundle 140 where a second set of optical fibers collects this reflected radiation and the spectrometer 1
Carry to 43.

Spectrometer 143 stores and analyzes this diffusely reflected or reflected radiation, or further spectroscope 143.
Can transmit spectral data to a computer, which analyzes the data.

A particularly preferred spectrometer is the NIR Systems Model 6500 Spectrophotometer (Near Infrared Spectrophotometer) available from NIR Systems, Inc., 12101, Tech Spring, Silver Spring, 20904, Maryland, USA. A computer for analyzing this data is 8 Mb
Zeos 33MHz 80846DXP with built-in RAM
There is a personal computer such as C. This data is integrated into a computer using near infrared spectrum analysis software (NSAS). This NSAS is N
Spectroscopic instrument from IR system
nt) is an instrument control package. This data is then used by Cochit Palace, 24 Prime Park Road, Natick, Massachusetts, USA.
Mateworks, Inc.
hworks Inc. ) Is a software package available from Matlab.

FIG. 5 shows a schematic diagram of another type of known blender used to mix the components. In this other known blender, it is not necessary to rotate the blender container about the axis of rotation in mixing the components into a homogeneous mixture. Instead, in this blender, the inside of the container is agitated (mixed) like a blade or a stirrer.
It is necessary to stir with the equipment and mix the components to form a homogeneous mixture. A ribbon blender is an example of a known blender using a blade. A core blender is an example of a known blender using a stirrer. In addition to mixing powders and liquids, these blenders are also capable of mixing components such as ointments and creams.

According to FIG. 5, the rectangular box 500 represents a known fixed blender. This fixed blender uses an internal stirrer to mix the ingredients into a homogeneous mixture. The blender 500 has a hole 502 in one of the walls 501. However, it is also possible to provide more holes in one or more walls. This hole must be open inside the blender 500 container. This is because the sensing means can bring radiation from the spectroscopic means to the mixture inside the blender container, and this reflected or transflected radiation can be integrated and analyzed.

FIG. 6A shows a hole 502 and a blender wall 501.
And the conducting means 140, the blender wall 501 is recessed into the container of the blender 500.
The holes 502 in the blender wall 501 are covered and sealed by a transparent barrier 503. This transparent barrier 50
3 is made of a material similar to that of the transparent window 137, and provides the same function as the transparent window 137. The first end of the conducting means 140 is in close proximity to, and preferably in contact with, the transparent barrier 503, and means 140 for conducting radiation.
The second end of the spectroscope 143 is shown in FIG. 1 and as described above.
Is removably attached to.

FIG. 6B shows a hole 502 and a blender wall 501.
2 shows another embodiment of the transmission means 140 and the transmission means 140. Hole 50
2 is covered and sealed by attaching the conducting means 140 to the blender wall 501 via the holes 502. The conducting means 140 projects into the container of the blender 500. The end of this conducting means 140 protruding into the interior of the container is covered by a transparent barrier 503.
Furthermore, the above-mentioned transflance probe 400 can be replaced with the transparent barrier 503.

FIG. 6C shows a hole 502 and a blender wall 501.
And an example of the spectroscope 143 are shown. In this embodiment, the transparent barrier 503 is a hole 5 in the blender wall 501.
02 is covered and sealed. A spectroscope 143 is disposed adjacent to the blender wall 501, and the aperture 147 in the spectroscope 143, through which the radiation is emitted and contained, is transparent barrier 50.
3 are arranged close to each other, preferably in abutting contact.

FIG. 6D shows a hole 502 and a blender wall 501.
And yet another embodiment of the conducting means 140 is shown. In this embodiment, a transparent barrier 503 covers and seals holes 502 in blender wall 501. The conducting means 140 is arranged such that its first end is close to and preferably in contact with the transparent barrier 503.

6A, 6B and 6D show that the conducting means 140 can be combined with the blender 500 to use the on-line acquisition of spectral data of the admixed mixture, which allows the efficacy of the drug mixture and 1 illustrates a preferred embodiment in which homogeneity can be determined. Spectrum acquisition can be accomplished in the same manner as described above with respect to the exemplary embodiment shown by the modified V-blender.

As shown in FIGS. 6A, 6B and 6D,
In the embodiment where the conducting means 140 is a fiber optic bundle, the fiber optic bundle 140 comprises two sets of optical fibers. The first set of optical fibers carries radiation from the spectrometer 143 to the mixture. The transparent barrier 503 allows the radiation emanating from the first set of optical fibers of the fiber optic bundle 140 to pass through the mixture of components without distortion. Radiation that comes into contact with this mixture is scattered and reflected in the case of solid mixtures and transflected in the case of liquids. Second
Sets of optical fibers collect the scattered, reflected or transflected radiation from the mixture and carry it to the spectrometer 143. The spectroscope 143 analyzes the radiation,
Alternatively, the spectroscope 143 also carries the data to the computer. The computer then analyzes this.

In FIG. 6C, the spectroscope 143 has a blender 50.
It shows an embodiment of the invention that does not require the conducting means 140, instead of being able to be placed adjacent to 0.
The radiation from the spectroscope 143 and the radiation reflected in a dispersed state from the mixture are not transmitted to the aperture 14 without the aid of the conducting means 140.
Pass 7.

In the preferred embodiment as shown in FIG. 7, hole 107 is sealingly sealed by shaft 180. The shaft 180 has a groove 182 therethrough, the shaft 180 having a first end and a second end. Hollow pipe 151 has a first end and a second end. The first end of the hollow pipe 151 is an optically transparent sealing means 1 such as a lens or transflexance probe 400.
It is sealed by 52. The lens used as the optically transparent sealing means 152 is made of a material similar to that of which the transparent sealing or sealing means 137 is made. The inner diameter of the shaft 180 is the hollow pipe 15
Larger than the outer diameter of 1, so that the hollow pipe is removably arranged on the shaft. First of the shaft 180
The end extends into the container 101 and is in contact with each component to be mixed in the container. Second of shaft 180
The ends are rotatably mounted through aligned holes in the first ball bearing pillow block 210 and the first support 128, thus the shaft 180 is aligned with the second shaft 111 and is flat and level. It forms the axis of rotation. This horizontal axis of rotation must be located well above the legs of the container 101, which causes the container 101 to rotate through the shaft 180 and the second shaft 1.
It is freely rotatable about an axis of rotation formed by 11 through an angle of 360 °. The fiber optic bundle 140 is disposed inside a hollow pipe 151, and if the first end of the hollow pipe 151 is sealed by a transflance probe 400, the first end of the fiber optic bundle 140 is a lens 152. Alternatively, the transparent lens 410 is contacted. The hollow pipe 151 has a shaft 180
Is removably disposed in the groove 182 of the hollow pipe 151 and the first end of the hollow pipe 151 is preferably, but not necessarily, disposed beyond the first end of the shaft 180. A self-lubricating seal 185, such as Teflon (trademark), is occluded between the first end of the hollow pipe 151 and the first end of the shaft 180, and each component to be mixed in the container 101. Does not leak into the groove 182 of the shaft 180. This seal 185 is self-lubricating and the shaft 180
Rotate with and thus seal 185 is hollow pipe 1
Rotating around the first end of 51, the hollow pipe 151 remains fixed.

In another preferred embodiment of the invention,
As shown in FIG. 8, means 150 for detecting the rotational (angle) position of the container 101 is incorporated in the mixing means. Examples of the rotation (angle) position detecting means include an absolute digital axis encoder, a pulse encoder,
There are optical encoders and analog encoders.
This means is not limited to this, and other rotation (angle) position detecting means is not excluded. The post 155 shown is generally U with a first leg and a second leg.
The first leg is attached to the rotational position detecting means 150. The second leg is attached to the second support 131. Further, FIG. 8 shows the first connecting shaft 160a and the second connecting shaft 160b. The first connecting shaft 160a has a first end and a second end. The second connecting shaft 160b has a first end and a second end. The first end of the first connecting shaft 160a is attached to the second shaft 111 horizontally and in a straight line,
The first end of the first connecting shaft 160a rotates together with the rotation of the second shaft 111. The second end of the first connecting shaft 160a is flexibly and fixedly connected to the coupling 165.
The first end of the second connecting shaft 160b is flexibly and fixedly connected to the coupling 165, whereby the second end of the first connecting shaft 160a and the first end of the second connecting shaft 160b are connected. The ends are opposite each other but do not touch each other. The second end of the second connecting shaft 160b is attached to the rotational position detecting means 150. Coupling 16
5 is a rotational force from the first connecting shaft 160a to the second connecting shaft 160a.
b to the first connecting shaft 160a and the second connecting shaft 1
60b is rotating at the same time as the rotation of the second shaft 111.
Further, the coupling 165 flexibly and fixedly holds the first connecting shaft 160a and the second connecting shaft 160b, and while the second shaft 111 is rotating, the first connecting shaft 160a and the second connecting shaft 160a.
Rotational stress with the connecting shaft 160b is reduced. The rotational position sensing means 150 is interfaced to a relay box by a first set of connecting lines 170, which in turn is interfaced to a data acquisition and control computer 163 by a second set of connecting lines. This second set of interconnects relays information from the relay box to the data acquisition and control computer 163. In the embodiment where the rotational position sensing means 150 is an absolute digital encoder, the relay box translates the digital signal from the absolute digital encoder to ASCII number. This ASCII number indicates the rotational position of the container 101 in an angle. This ASCII number is transmitted to the data acquisition and control computer 163 by the second set of connecting lines.
The data acquisition and control computer 163 is interfaced to the spectroscope 143 by a third set of connecting wires 173. When the container 101 rotates, the rotation of the second connecting shaft 60b is detected by the rotational position detecting means 150, and the rotational position detecting means 150 relays the rotational position of the container 101 via the first set of connecting wires 170. Tell the box. The relay box then conveys information to the data acquisition and control computer 163 via the second set of connecting lines. A data acquisition and control computer 163 using control software such as Labview available from National Instruments, Inc. of Austin, Texas 78730, USA.
Collects the spectral data by the spectroscope 143 in the container 10
Rotation angle position detection means 1 translated into 1 rotation position
It is tuned to a predetermined position of 50. As a result, the spectroscopic data is steadily accumulated at a predetermined rotation position of the container 101.
A point at one or more predetermined rotational positions of the container 101 will be selected to collect the spectral data. Accumulation of spectral data by the spectroscope 143 is performed by the window (Windo) available at most computer supply stores.
ws) 3.1 and WINSUS (WI) available from NIR Systems, Inc. of Silver Spring, Md.
This is accomplished by a software program such as Microsoft such as NSAS). WINSA
S) program is based on Microsoft Windows (Wi
DDW (Dy) which is an essential feature of Windows 3.1.
A control software program such as Labview is instructed when to start the collection of the spectroscopic data via the Native Data Exchange. Further, the data acquisition and control computer 163 is interfaced to the relay box by a fourth set of connecting wires. The rotating means 216 can be manually controlled or can be controlled by the relay box. The interface of the data acquisition and control computer 163 to the relay box, when the data acquisition and control computer 163 determines by a mathematical analysis described below that each of the components to be mixed has finally reached a homogeneous state, The data acquisition and control computer 163 allows the rotating means 216 to be rotated or stationary. This final homogeneous state is DD
Transmitting the spectroscopic data collected by Winsus to another software program, such as InStep, available from Infometrics, Inc. of Seattle, Washington, USA, via E. Determined by This spectroscopic data is then used for the above-mentioned infometrics (In
Pyrote (Pir) available from Fometrix
a pre-calculated model (pre-cal) developed using a software program such as ouette.
Analyzed with the use of integrated models).
The rotating means 216 is stopped after a desired time before the respective components to be mixed reach the final homogeneous state, and the sample is taken out of the container and analyzed. Also, the rotating means 216 may be stopped for other reasons intended by the user. Each set of connecting lines described above is a device capable of transmitting an optical or electronic signal.

The data acquisition and control computer used in this embodiment is a 33 Mb with 16 Mb RAM.
Hz, 486DX, Toshiba T6400DX. However, it could be a computer of similar or greater improved capacity.

The initial spectrum of the mixture will be closest to the spectrum of each of the components of the mixture. Once the mixing device has begun mixing each component, the spectrum of the mixture will appear similar to that of a homogeneous mixture, rather than the spectra of the individual components. Eventually this spectrum will converge to that of a homogeneous mixture. This analytical method is used to determine the distribution of each component, active and inactive, within the mixture. Thus, the device of the present invention can determine the homogeneity throughout the mixture.

Calculations are made to estimate when all the components of a mixture are homogenized by measuring the variation of a group of spectra as a function of time. For example, groups of 50 spectra are taken at 1 minute intervals. Spectrum 1-5,
Calculate the standard deviation of the wavelength of 2-6, 3-7, etc. The standard deviation of the spectrum calculated in this way indicates the most fluctuating spectral region. Calculation of the variability of the individual deviation spectra will then give a standard for the total variability of the mixture as a function of time. It is considered that the mixture became homogeneous when the total amount of mutation decreased to a certain value. On the other hand, the computer can program the spectra of known homogeneous mixtures. Mixing is complete when the spectrum of the running mixture matches that of a known homogeneous mixture.

1 to 4, FIG. 5, FIG. 6a to FIG. 6d, and FIG.
And the embodiment of the invention shown in FIG. 8 allows spectra of each component mixture to be collected while the blender is in motion. Therefore, the device of the present invention can prevent downtime, which is a fundamental drawback of the conventional device. The device according to the invention allows on-line detection of the homogeneity and effectiveness of the mixture, a feature which was not available in the known devices.

Furthermore, the device according to the invention can be modified so that it can be applied to more than one detection means consisting of a spectroscopic means selectively equipped with conduction means as described above. Of. The device of the invention with multiple spectroscopic means can be coupled with similar types of spectroscopic means or with different types of spectroscopic means. The modified V-blender, which is an exemplary device of the present invention, may be modified to accommodate two spectroscopic means by using a hollow second shaft. The conducting means may be arranged in the hollow second shaft in a manner similar to that described for the fiber optic bundle in the hole of the first shaft described above.

The known blender of type 500 further comprises
It can be modified to accommodate multiple spectroscopic means by forming as many holes as desired at the desired locations in the blender wall. Is each of these many holes capable of being fitted with a conducting means which will be connected to a spectroscopic means as shown in FIGS. 6A, 6B and 6D and as described above? Or each hole is adapted to be able to be abutted by spectroscopic means as shown in FIG. 6C and as described above, or FIG.
It is possible to have a combination of the embodiments shown in FIGS.

[0045]

The advantage of using one or more detection means of the same type as the device of the invention is that
It is possible to learn the spectral properties of the mixture from more than one position. This embodiment of the invention further comprises
It is possible to ensure that the mixture is homogenized throughout the container.

The advantages of using another type of detection means in the device of the invention are as follows. In the formulation of the drug, there are various components as described above. Some components can only be detected by one type of radiation, such as near-infrared radiation. Also, other components of these drug formulations can only be detected by other types of radiation than infrared, such as visible radiation. In such a case, it may have two spectroscopic means connected to the mixing means, namely a near-infrared spectrophotometer as the first spectroscopic means and a visible spectrophotometer as the second spectroscopic means. It is advantageous. Each spectrophotometer thus detects the spectroscopic properties of the components of the drug formulation that are detectable.

The device of the invention may also be fitted with an alarm device which signals the operator of the device of the invention when the mixture reaches the homogeneity and efficacy endpoints. In addition, the system may include a device that automatically activates to stop when the mixture reaches the homogeneity and efficacy endpoints.

The invention is not to be limited to the particular embodiments shown and described herein, but various changes and modifications can be made without departing from the spirit and scope of this novel concept as defined by the appended claims. It will be appreciated that improvements are possible.

[Brief description of drawings]

FIG. 1 shows a side view of an exemplary device of the present invention with a cross-sectional view of container 101 and a first shaft 125.

FIG. 2 is a top view of the device of FIG.

FIG. 3 is an enlarged view of FIG. 1, showing part of the container and its attachment to the spectroscopic means.

FIG. 4 is a side view of a transflance probe attached to a shaft.

FIG. 5 is a representative side view of a known blender with internal mixing means (eg ribbon blender or core blender).

6A-6D are cross-sectional views taken along line 6a of FIG. 5 showing the blender device, showing various means for connecting the sensing means to the blender device. is there.

FIG. 7 is an enlarged sectional view of the present embodiment showing the container, the shaft, and various members within the shaft.

FIG. 8 shows another embodiment of the device according to the invention with means for detecting the rotational position of the container.

[Explanation of symbols]

101: Container 104: Surface wall 107: Hole 111: Second shaft 115, 119: Opening 122: Bottom cover 123: Bottom stopper 125: First shaft 128: First support 131: Second support 134: Hole 137 : Sealing means (transparent window) 140: Conducting means (fiber engineering bundle) 141: Sleeve 143: Spectrometer 147: Opening 150: Rotation angle position detecting means 151: Hollow pipe 152: Sealing means 155: Support 160a: First connecting shaft 160b: second
Connection shaft 163: Data acquisition and control computer 165: Coupling 170, 173: Connection line 180: Shaft 182: Groove 185: Seal 201: First hollow leg portion 204: Second hollow leg portion 207: Top cover 208: Top stop 208 Gold 210: First ball bearing pillow block 213: Second ball bearing pillow block 216: Rotating means 400: Transflanceance probe 405: Housing 410: Transparent lens 415: Reflector 420: Space 500: Box (Blender) 501: Wall 502: Hole 503: Barrier

Claims (21)

[Claims] 1. An apparatus for mixing a mixture of substances into a homogeneous mixture and for detecting the homogeneity of the mixture on-line, comprising: (a) a mixing means for mixing the mixture of substances; b) a detection device for detecting the homogeneity of the mixture on-line, and a device for mixing and detecting the mixture, which comprises: 2. A device for mixing and detecting the mixture of claim 1, wherein: (a) said mixing means comprises a container,
2. Mixing the mixture of claim 1, wherein (b) said container has a hole, and (c) a transparent sealing means for sealing said hole is arranged between said hole and said sensing means. Device to detect. 3. A spectroscopic means for measuring spectroscopic properties of a mixture of said substances, wherein said sensing means has (a) an opening through which radiation is emitted and received. A conducting means for conducting radiation from the spectroscopic means to the mixture and then conducting reflected or transflected radiation to the spectroscopic means, the means being connected to the hole of the spectroscopic means. 3. A device for mixing and sensing the mixture of claim 2 comprising: 4. A device for mixing and detecting the mixture according to claim 3, comprising: (a) the container having a rotating shaft,
(B) means for rotating around the rotation axis of the container, the rotation means being connected to the container, (c) the rotation axis having a hole, and (d) being inserted into the hole. A device for mixing and sensing a mixture according to claim 3 including: said conducting means. 5. A device for mixing and detecting the mixture of claim 4, wherein (a) said mixing means comprises a first support and a second support.
A support, a first support has lateral holes extending therethrough, a second support has lateral holes passing therethrough, and (b) the container is Two hollow leg portions are formed into a first hollow opening, and the first hollow leg portion and the second hollow leg portion are converged at an angle so as to form the container in a V shape. The hollow leg and the second hollow leg have an outwardly facing surface wall, and (c) the container is disposed via the outwardly facing surface wall of the first hollow leg. And (d) a first ball bearing pillow block having a lateral hole extending therethrough, the first ball bearing pillow block being between the container and the first support. Positioned and attached to the first support, the holes in the first ball bearing pillow block are aligned with the holes in the first support, ) A second ball bearing pillow block has a lateral hole extending therethrough, the second ball bearing pillow block being disposed between the container and the second support and to the second support. Mounted, the hole of the second ball bearing pillow block is aligned with the hole of the second support, and (f) the first shaft has a first end and a second end and has a hole therethrough. And
(G) the transparent sealing means is selected from the group consisting of a transparent window and a transflectance probe, the transparent sealing means covering and sealing the bore of the first shaft at the first end; h) a second shaft has a first end and a second end, and (i) the first end of the second shaft is attached to the outwardly facing surface wall of the second hollow leg of the container. (J) The second end of the second shaft is rotatably mounted via the alignment hole of the second support and the second ball bearing pillow block, and the second end of the second shaft is mounted. An end is connected to the rotating means, (k) a first end of the first shaft engages the container through the hole, and the transparent sealing means is inside the first hollow leg of the container. And (l) the second end of the first shaft has the first support and the first ball bearing pillow. Is rotatably mounted so as to be aligned with the second axis through an alignment hole in the frame, (m) the conduction means has a first end and a second end, and (n) the conduction. Means are removably disposed within the bore of the first shaft;
5. A device for mixing and sensing a mixture according to claim 4, wherein the first end of the conducting means impinges on the transparent window and the second end of the conducting means is mounted in the opening of the spectroscopic means. 6. An apparatus for mixing and sensing a mixture according to claim 5, wherein: (a) said container is provided with a plurality of openings for loading a mixture of substances to be mixed and for discharging a homogenized mixture. An apparatus for mixing and detecting a mixture as claimed in claim 5, having (b) the conducting means is a fiber optic bundle and (c) the rotating means is an electric motor. 7. The apparatus for mixing and sensing a mixture of claim 4 wherein said mixing means is a V-blender, ribbon blender, or core blender. 8. The mixture of claim 7 wherein the sensing means is a near infrared spectrophotometer, an ultraviolet spectrophotometer, a visible light spectrophotometer, a Raman spectrophotometer, or a mid-range infrared spectrophotometer. And a device to detect. 9. An apparatus for mixing and detecting a mixture according to claim 1, wherein (a) said mixing means has a container, (b) said container has a hole, and (c) ) A device for mixing and detecting a mixture as claimed in claim 1, wherein the shaft is the container sealing the hole and the shaft is the axis of rotation. 10. A device for mixing and detecting a mixture according to claim 9, wherein said detection means comprises (a) an opening through which radiation is emitted and received. A spectroscopic means for measuring copic properties, and (b) conducting radiation from the spectroscopic means to the mixture, and then conducting reflected or transflected radiation to the spectroscopic means. 10. A device for mixing and sensing a mixture according to claim 9 comprising: a conducting means, the conducting means being connected to the hole of the spectroscopic means. 11. A device for mixing and detecting a mixture according to claim 10, wherein (a) means for rotating about the axis of said container are connected to said container, and (b) said shaft therethrough. 11. A device for mixing and sensing a mixture as claimed in claim 10 having a tunnel therethrough and (c) the conducting means being removably plugged into the tunnel. 12. An apparatus for mixing and detecting a mixture according to claim 11, wherein (a) said mixing means comprises a first support and a second support, the first support penetrating therethrough. And a second support has a lateral hole penetrating therethrough, and (b) the container comprises a first hollow opening that opens to a second hollow leg. The first hollow leg and the second hollow leg
The hollow leg is converging at an angle that makes the container V-shaped, and the first hollow leg and the second hollow leg have a surface wall facing outward, (c) ) The container has a hole arranged through an outer surface wall of the first hollow leg, and (d) a first ball bearing pillow block has a side hole extending therethrough. The first ball bearing pillow block is disposed between the container and the first support and is attached to the first support, and the hole of the first ball bearing pillow block is formed in the first support. (E) a second ball bearing pillow block having a lateral hole therethrough, the second ball bearing pillow block being between the container and the second support. A second ball positioned and attached to the second support A ring pillow hole block second
Aligned with the holes in the support, (f) the first axis has a first end and a second end, and has a tunnel therethrough, and (g) the second axis is the first end. And a second end, the first end of the second shaft being attached to the outwardly facing surface wall of the second hollow leg of the container, the second end of the second shaft. Is rotatably mounted via a matching hole between the second support and the second ball bearing pillow block, and the second end of the second shaft is connected to the rotating means.
(H) The first end of the shaft is engaged with the container through the hole, and the first end of the shaft projects into the first hollow leg of the container, Two ends are the first support and the first support.
The ball bearing pillow block is rotatably mounted so as to be aligned with the second shaft through an alignment hole with the ball bearing pillow block.
(I) The hollow pipe has a first end and a second open end, the first end being sealed by an optically transparent sealing means selected from the group consisting of a lens and a transflexance probe. , (J) the conduction means is first
An end and a second end, the conducting means being removably disposed in the hollow pipe, the first end of the conducting means abutting the optically transparent sealing means, and the conducting means. A second end of the hollow pipe is attached to an opening of the spectroscopic means, and (k) the hollow pipe is removably disposed in a tunnel of the shaft, the first end of the hollow pipe being the first end of the shaft. Extends beyond the end, (l) a seal is occluded between the hollow pipe and the shaft, and (m) the post has a first leg and a second leg. A first leg of the column is attached to the second support, a second leg of the column is attached to a means for detecting a rotational position, and (n) the first connecting shaft has a first end and A second end, the first end being mounted horizontally and in-line with respect to the second axis. And attached, wherein the second end is fixedly and flexibly connected against the joint, (o)
The second connecting shaft has a first end and a second end, and the first end of the second connecting shaft is fixed to the joint facing the second end of the first connecting shaft. And connected flexibly,
Device for mixing and detecting a mixture according to claim 11, wherein the second end of the second connecting shaft is attached to a means for detecting a rotational position. 13. A device for mixing and detecting the mixture of claim 12, wherein (a) the means for detecting rotational position is interfaced to the relay box by a first set of connecting wires, and (b). The relay box is interfaced to the data acquisition and control computer by a second set of connecting lines, and (c) the data acquisition and control computer is interfaced to the spectroscopic means by a third set of connecting lines. An apparatus for mixing and detecting the mixture of claim 12. 14. A device for mixing and sensing a mixture as claimed in claim 13 wherein: (a) said container is provided with a plurality of openings for loading a mixture of substances to be mixed and for discharging a homogenized mixture. 14. Mixing the mixture of claim 13, wherein: (b) the conducting means is a fiber optic bundle, (c) the rotating means is an electric motor, and (d) the seal is made of Teflon. Devices that detect and detect. 15. The apparatus for mixing and sensing the mixture of claim 14, wherein: (a) said data acquisition and control computer is interfaced to said relay box by a fourth set of connecting wires; 15. A device for mixing and detecting a mixture according to claim 14 wherein said rotating means is controlled by said relay box. 16. The apparatus for mixing and sensing a mixture of claim 11 wherein said mixing means is a V-blender, ribbon blender, or core blender. 17. The mixture of claim 16 wherein said sensing means is a near infrared spectrophotometer, an ultraviolet spectrophotometer, a visible light spectrophotometer, a Raman spectrophotometer, or a mid-range infrared spectrophotometer. And a device to detect. 18. A method of mixing a mixture of substances into a homogeneous mixture and detecting the homogeneity of the mixture online, comprising: (a) the mixture of substances to be mixed having holes. Into the container of the mixing device, (b) mixing the mixture of the substances, (c) during the mixing process, the spectroscopic properties of the homogeneous mixture are in a final homogeneous state. Until or until the spectroscopic properties converge, the on-line detection of the spectroscopic properties of the mixture by a detection means for detecting the homogeneity and effectiveness of the mixture online. How to mix and detect. 19. The method of claim 18 wherein the detection of the spectroscopic characteristics of the mixture on-line during the mixing step is synchronized with the detection of the rotational position of the container by the rotational position detecting means. A method of mixing and detecting a mixture. 20. A spectroscopic means, said sensing means having an opening through which radiation is emitted and received; and a radiation conducting to said mixture from said spectroscopic means to said spectroscopic means. A conducting means for conducting reflected or transflected radiation, the conducting means having a first end and a second end, the first end to the opening of the spectroscopic means and the second end to the container. 19. A method of mixing and detecting a mixture of claim 18 including: a conducting means connected to the hole of. 21. The detection means comprises spectroscopic means having an opening through which the radiation is emitted, the radiation reflected or transflected from the mixture is contained, and the opening of the detection means is the container. 19. A method of mixing and detecting the mixture of claim 18 impinging on the holes of the.