CA2126826C - Apparatus for mixing and detecting on-line homogeneity - Google Patents
Apparatus for mixing and detecting on-line homogeneityInfo
- Publication number
- CA2126826C CA2126826C CA002126826A CA2126826A CA2126826C CA 2126826 C CA2126826 C CA 2126826C CA 002126826 A CA002126826 A CA 002126826A CA 2126826 A CA2126826 A CA 2126826A CA 2126826 C CA2126826 C CA 2126826C
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- Canada
- Prior art keywords
- container
- spectroscopic
- support
- mixture
- axle
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000002156 mixing Methods 0.000 title claims abstract description 48
- 239000000203 mixture Substances 0.000 claims abstract description 116
- 239000008240 homogeneous mixture Substances 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 19
- 230000005855 radiation Effects 0.000 claims description 43
- 238000001514 detection method Methods 0.000 claims description 24
- 239000000835 fiber Substances 0.000 claims description 23
- 238000007789 sealing Methods 0.000 claims description 14
- 238000004891 communication Methods 0.000 claims description 13
- 239000000523 sample Substances 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 8
- 230000008878 coupling Effects 0.000 claims description 6
- 238000010168 coupling process Methods 0.000 claims description 6
- 238000005859 coupling reaction Methods 0.000 claims description 6
- 238000007599 discharging Methods 0.000 claims description 4
- 238000001069 Raman spectroscopy Methods 0.000 claims description 3
- 239000004809 Teflon Substances 0.000 claims 1
- 229920006362 Teflon® Polymers 0.000 claims 1
- 230000001360 synchronised effect Effects 0.000 claims 1
- BFKJFAAPBSQJPD-UHFFFAOYSA-N tetrafluoroethene Chemical compound FC(F)=C(F)F BFKJFAAPBSQJPD-UHFFFAOYSA-N 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 19
- 238000001228 spectrum Methods 0.000 description 19
- 230000004888 barrier function Effects 0.000 description 10
- 239000013307 optical fiber Substances 0.000 description 8
- 239000007788 liquid Substances 0.000 description 7
- 238000004611 spectroscopical analysis Methods 0.000 description 7
- 230000003595 spectral effect Effects 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000008901 benefit Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000010453 quartz Substances 0.000 description 2
- 238000005204 segregation Methods 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229910052709 silver Inorganic materials 0.000 description 2
- 239000004332 silver Substances 0.000 description 2
- 239000008247 solid mixture Substances 0.000 description 2
- 239000011800 void material Substances 0.000 description 2
- 238000013459 approach Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229910052594 sapphire Inorganic materials 0.000 description 1
- 239000010980 sapphire Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000012956 testing procedure Methods 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F29/00—Mixers with rotating receptacles
- B01F29/20—Mixers with rotating receptacles with receptacles rotating about an axis at an angle to their longitudinal axis
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F29/00—Mixers with rotating receptacles
- B01F29/40—Parts or components, e.g. receptacles, feeding or discharging means
- B01F29/401—Receptacles, e.g. provided with liners
- B01F29/4011—Receptacles, e.g. provided with liners characterised by the shape or cross-section of the receptacle, e.g. of Y-, Z -, S -, or X shape
- B01F29/40118—V or W shapes
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F29/00—Mixers with rotating receptacles
- B01F29/40—Parts or components, e.g. receptacles, feeding or discharging means
- B01F29/403—Disposition of the rotor axis
- B01F29/4036—Disposition of the rotor axis with a plurality of rotating receptacles
- B01F29/40363—Disposition of the rotor axis with a plurality of rotating receptacles having perpendicular axes
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F29/00—Mixers with rotating receptacles
- B01F29/60—Mixers with rotating receptacles rotating about a horizontal or inclined axis, e.g. drum mixers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F29/00—Mixers with rotating receptacles
- B01F29/60—Mixers with rotating receptacles rotating about a horizontal or inclined axis, e.g. drum mixers
- B01F29/62—Mixers with rotating receptacles rotating about a horizontal or inclined axis, e.g. drum mixers without bars, i.e. without mixing elements; characterised by the shape or cross section of the receptacle, e.g. of Y-, Z-, S- or X- shape; with cylindrical receptacles rotating about an axis at an angle to their longitudinal axis
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
- B01F35/20—Measuring; Control or regulation
- B01F35/21—Measuring
- B01F35/213—Measuring of the properties of the mixtures, e.g. temperature, density or colour
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
- B01F35/71—Feed mechanisms
- B01F35/717—Feed mechanisms characterised by the means for feeding the components to the mixer
- B01F35/71705—Feed mechanisms characterised by the means for feeding the components to the mixer using belts
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
- B01F35/75—Discharge mechanisms
- B01F35/754—Discharge mechanisms characterised by the means for discharging the components from the mixer
- B01F35/7547—Discharge mechanisms characterised by the means for discharging the components from the mixer using valves, gates, orifices or openings
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
- B01F35/71—Feed mechanisms
Landscapes
- Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Physics & Mathematics (AREA)
- General Health & Medical Sciences (AREA)
- Geometry (AREA)
- Veterinary Medicine (AREA)
- Accessories For Mixers (AREA)
- Investigating Or Analysing Materials By Optical Means (AREA)
- Medical Preparation Storing Or Oral Administration Devices (AREA)
- Mixers With Rotating Receptacles And Mixers With Vibration Mechanisms (AREA)
- Continuous Casting (AREA)
- Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
Abstract
This invention relates to an apparatus for mixing compositions of matter into a 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.
Description
~ 2126g26 -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 ; 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 ~ - 3a -t 72222-237 ~126~26 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 "_, 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 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 212~826 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 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~
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 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 _ 212G826 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.
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 ; 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 ~ - 3a -t 72222-237 ~126~26 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 "_, 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 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 212~826 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 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~
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 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 _ 212G826 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.
Claims (21)
1. An apparatus for mixing compositions of matter into a homogeneous 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.
(a) mixing means for mixing said compositions of matter; and (b) spectroscopic detection means for detecting on-line the homogeneity of said mixture.
2. The apparatus of claim 1 wherein:
(a) said mixing means having a container;
(b) said container having an aperture; and (c) a pellucid sealing means for sealing said aperture disposed between said aperture and said spectroscopic detection means.
(a) said mixing means having a container;
(b) said container having an aperture; and (c) a pellucid sealing means for sealing said aperture disposed between said aperture and said spectroscopic detection means.
3. The apparatus according to claim 2 wherein said spectroscopic detection means comprises:
(a) spectroscopic means for measuring the spectroscopic characteristics of said compositions of matter having an opening from which radiation emanates and is received; and (b) conduction means for conducting radiation to said mixture from said spectroscopic means and then conducting reflected or transflected radiation to said spectroscopic means, said conduction means connected to said opening of said spectroscopic means.
(a) spectroscopic means for measuring the spectroscopic characteristics of said compositions of matter having an opening from which radiation emanates and is received; and (b) conduction means for conducting radiation to said mixture from said spectroscopic means and then conducting reflected or transflected radiation to said spectroscopic means, said conduction means connected to said opening of said spectroscopic means.
4.
The apparatus according to claim 3 wherein:
(a) said container has an axis of rotation;
(b) means for rotation about said axis of said container, said means for rotation connected to said container;
(c) said axis of rotation having a bore; and (d) said conduction means inserted in said bore.
The apparatus according to claim 3 wherein:
(a) said container has an axis of rotation;
(b) means for rotation about said axis of said container, said means for rotation connected to said container;
(c) said axis of rotation having a bore; and (d) said conduction means inserted in said bore.
5. The apparatus according to claim 4, wherein:
(a) said mixing means has a first support and a second support, said first support has a lateral hole therethrough and said second support has a lateral hole therethrough;
(b) said container formed from a first hollow leg open to a second hollow leg, said first hollow leg and second hollow leg converging at an angle giving said container - 15a -a "V" shape, each of said first hollow leg and said second hollow leg has an outward facing surface wall;
(c) said container has an aperture disposed through the outward facing surface wall of said first hollow leg;
(d) a first ballbearing pillow block having a lateral hole therethrough, said first ballbearing pillow block disposed between said container and said first support and attached to said first support, wherein said first ballbearing pillow block's hole is aligned with said first support's hole;
(e) a second ballbearing pillow block having a lateral hole therethrough, said second ballbearing pillow block disposed between said container and said second support and attached to said second support, wherein said second ballbearing pillow block's hole is aligned with said second support's hole;
(f) a first axle having a first end and a second end and having a bore therethrough;
(9) said pellucid sealing means is selected from the group consisting of a pellucid window and a transflectance probe, said pellucid sealing means covers and seals said bore of first axle at said first end;
(h) a second axle having a first end and a second end;
(i) said second axle's first end attached to said outward facing surface wall ofsaid container's second hollow leg;
(j) said second axle's second end rotatably mounted through said aligned holes of said second support and said second ballbearing pillow block and said second axle's second end connected to said means for rotation;
(k) said first axle's first end engaged to said container through said aperture,said pellucid sealing means protruding inside said container's first hollow leg;(l) said first axle's second end rotatably mounted through said aligned holes ofsaid first support and said first ballbearing pillow block in alignment with said second axle;
(m) said conduction means having a first end and a second end; and (n) said conduction means removably disposed within said first axle's bore, saidconduction means' first end abutting said pellucid window and said conduction means' second end attached to said spectroscopic means' opening.
(a) said mixing means has a first support and a second support, said first support has a lateral hole therethrough and said second support has a lateral hole therethrough;
(b) said container formed from a first hollow leg open to a second hollow leg, said first hollow leg and second hollow leg converging at an angle giving said container - 15a -a "V" shape, each of said first hollow leg and said second hollow leg has an outward facing surface wall;
(c) said container has an aperture disposed through the outward facing surface wall of said first hollow leg;
(d) a first ballbearing pillow block having a lateral hole therethrough, said first ballbearing pillow block disposed between said container and said first support and attached to said first support, wherein said first ballbearing pillow block's hole is aligned with said first support's hole;
(e) a second ballbearing pillow block having a lateral hole therethrough, said second ballbearing pillow block disposed between said container and said second support and attached to said second support, wherein said second ballbearing pillow block's hole is aligned with said second support's hole;
(f) a first axle having a first end and a second end and having a bore therethrough;
(9) said pellucid sealing means is selected from the group consisting of a pellucid window and a transflectance probe, said pellucid sealing means covers and seals said bore of first axle at said first end;
(h) a second axle having a first end and a second end;
(i) said second axle's first end attached to said outward facing surface wall ofsaid container's second hollow leg;
(j) said second axle's second end rotatably mounted through said aligned holes of said second support and said second ballbearing pillow block and said second axle's second end connected to said means for rotation;
(k) said first axle's first end engaged to said container through said aperture,said pellucid sealing means protruding inside said container's first hollow leg;(l) said first axle's second end rotatably mounted through said aligned holes ofsaid first support and said first ballbearing pillow block in alignment with said second axle;
(m) said conduction means having a first end and a second end; and (n) said conduction means removably disposed within said first axle's bore, saidconduction means' first end abutting said pellucid window and said conduction means' second end attached to said spectroscopic means' opening.
6. The apparatus according to claim 5 wherein:
(a) said container has a plurality of openings for loading compositions of matter which are to be mixed and discharging the homogeneous mixture;
(b) said conduction means is a fiber optic bundle; and (c) said means for rotation is an electric motor.
(a) said container has a plurality of openings for loading compositions of matter which are to be mixed and discharging the homogeneous mixture;
(b) said conduction means is a fiber optic bundle; and (c) said means for rotation is an electric motor.
7. The apparatus according to claim 4 wherein said mixing means is a V-blender, a ribbon blender or a core blender.
8. The apparatus according to claim 7 wherein said detection means is a near infrared spectrophotometer, an ultraviolet spectrophotometer, a visible spectrophotometer, a Raman spectrophotometer, or a mid-range infrared spectrophotometer.
9. The apparatus according to claim 1 wherein:
(a) said mixing means having a container;
(b) said container having an aperture; and (c) an arbor seals said aperture of said container and is an axis of rotation.
(a) said mixing means having a container;
(b) said container having an aperture; and (c) an arbor seals said aperture of said container and is an axis of rotation.
10. The apparatus according to claim 9 wherein said detection means comprises:
(a) spectroscopic means for measuring the spectroscopic characteristics of said compositions of matter having an opening from which the radiation emanates and is received; and (b) conduction means for conducting radiation to said mixture from said spectroscopic means and then conducting reflected or transflected radiation to said spectroscopic means, said conduction means connected to said opening of said spectroscopic means.
(a) spectroscopic means for measuring the spectroscopic characteristics of said compositions of matter having an opening from which the radiation emanates and is received; and (b) conduction means for conducting radiation to said mixture from said spectroscopic means and then conducting reflected or transflected radiation to said spectroscopic means, said conduction means connected to said opening of said spectroscopic means.
11. The apparatus according to claim 10 wherein:
(a) means for rotation about said arbor of said container, said means for rotation connected to said container;
(b) said arbor having a tunnel therethrough; and (c) said conduction means removably inserted in said tunnel.
(a) means for rotation about said arbor of said container, said means for rotation connected to said container;
(b) said arbor having a tunnel therethrough; and (c) said conduction means removably inserted in said tunnel.
12. The apparatus according to claim 11 wherein:
(a) said mixing means has a first support and a second support, said first support has a lateral hole therethrough and said second support has a lateral hole therethrough;
(b) said container formed from a first hollow leg open to a second hollow leg, said first hollow leg and second hollow leg converging at an angle giving said container a "V" shape, each of said first hollow leg and said second hollow leg has an outward facing surface wall;
(c) said container has an aperture disposed through the outward facing surface wall of said first hollow leg;
(d) a first ballbearing pillow block having a lateral hole therethrough, said first ballbearing pillow block disposed between said container and said first support and attached to said first support, wherein said first ballbearing pillow block's hole is aligned with said first support's hole;
(e) a second ballbearing pillow block having a lateral hole therethrough, said second ballbearing pillow block disposed between said container and said second support and attached to said second support, wherein said second ballbearing pillow block's hole is aligned with said second support's hole;
(f) said arbor having a first end and a second end and having a tunnel therethrough;
(g) a second axle having a first end and a second end, said second axle's first end attached to said outward facing surface wall of said container's second hollow leg, said second axle's second end rotatably mounted through said aligned holes of said second support and said second ballbearing pillow block and said second axle's second end connected to said means for rotation;
(h) said arbor's first end engaged to said container through said aperture, saidarbor's first end protruding inside said container's first hollow leg, said arbor's second end rotatably mounted through said aligned holes of said first support and said first ballbearing pillow block in alignment with said second axle;
(i) a hollow pipe having a first end and a second open end, said first end sealed by an optically transparent sealing means selected from the group consisting of a lens and a transflectance probe;
a) said conduction means having a first end and a second end, said conduction means removably disposed within said hollow pipe with said first end of said conduction means abutting said optically transparent sealing means and said conduction means' second end attached to said spectroscopic means' opening;
(k) said hollow pipe removably disposed within said arbor's tunnel, said hollow pipe's first end extending beyond said arbor's first end;
(l) a seal occlusively disposed between said hollow pipe and said arbor;
(m) a brace having a first leg and a second leg, said first leg of said brace attached to said second support and said second leg of said brace attached to a means for detecting rotational position;
(n) a first connecting shaft having a first end and a second end, said first endattached horizontally and in-line to said second axle, said second end fixedly and flexibly connected to a coupling; and (o) a second connecting shaft having a first end and a second end, said first end of said second connecting shaft fixedly and flexibly connected to said coupling facing said second end of said first connecting shaft, said second end of said second connecting shaft attached to means for detecting rotational position.
(a) said mixing means has a first support and a second support, said first support has a lateral hole therethrough and said second support has a lateral hole therethrough;
(b) said container formed from a first hollow leg open to a second hollow leg, said first hollow leg and second hollow leg converging at an angle giving said container a "V" shape, each of said first hollow leg and said second hollow leg has an outward facing surface wall;
(c) said container has an aperture disposed through the outward facing surface wall of said first hollow leg;
(d) a first ballbearing pillow block having a lateral hole therethrough, said first ballbearing pillow block disposed between said container and said first support and attached to said first support, wherein said first ballbearing pillow block's hole is aligned with said first support's hole;
(e) a second ballbearing pillow block having a lateral hole therethrough, said second ballbearing pillow block disposed between said container and said second support and attached to said second support, wherein said second ballbearing pillow block's hole is aligned with said second support's hole;
(f) said arbor having a first end and a second end and having a tunnel therethrough;
(g) a second axle having a first end and a second end, said second axle's first end attached to said outward facing surface wall of said container's second hollow leg, said second axle's second end rotatably mounted through said aligned holes of said second support and said second ballbearing pillow block and said second axle's second end connected to said means for rotation;
(h) said arbor's first end engaged to said container through said aperture, saidarbor's first end protruding inside said container's first hollow leg, said arbor's second end rotatably mounted through said aligned holes of said first support and said first ballbearing pillow block in alignment with said second axle;
(i) a hollow pipe having a first end and a second open end, said first end sealed by an optically transparent sealing means selected from the group consisting of a lens and a transflectance probe;
a) said conduction means having a first end and a second end, said conduction means removably disposed within said hollow pipe with said first end of said conduction means abutting said optically transparent sealing means and said conduction means' second end attached to said spectroscopic means' opening;
(k) said hollow pipe removably disposed within said arbor's tunnel, said hollow pipe's first end extending beyond said arbor's first end;
(l) a seal occlusively disposed between said hollow pipe and said arbor;
(m) a brace having a first leg and a second leg, said first leg of said brace attached to said second support and said second leg of said brace attached to a means for detecting rotational position;
(n) a first connecting shaft having a first end and a second end, said first endattached horizontally and in-line to said second axle, said second end fixedly and flexibly connected to a coupling; and (o) a second connecting shaft having a first end and a second end, said first end of said second connecting shaft fixedly and flexibly connected to said coupling facing said second end of said first connecting shaft, said second end of said second connecting shaft attached to means for detecting rotational position.
13. The apparatus according to claim 12 wherein (a) said means for detecting rotational position interfaced to a relay box by a first set of communication wires;
(b) said relay box interfaced to a data acquisition and control computer by a second set of communication wires; and (c) said data acquisition and control computer interfaced to said spectroscopic means by a third set of communication wires.
(b) said relay box interfaced to a data acquisition and control computer by a second set of communication wires; and (c) said data acquisition and control computer interfaced to said spectroscopic means by a third set of communication wires.
14. The apparatus according to claim 13 wherein (a) said container has a plurality of openings for loading compositions of matter which are to be mixed and discharging the homogeneous mixture;
(b) said conduction means is a fiber optic bundle;
(c) said means for rotation is an electric motor; and (d) said seal is made of TEFLON~.
(b) said conduction means is a fiber optic bundle;
(c) said means for rotation is an electric motor; and (d) said seal is made of TEFLON~.
15. The apparatus according to claim 14 wherein (a) said data acquisition and control computer interfaced by a fourth set of communication wires to said relay box; and (b) said means for rotation is controlled by said relay box.
16. The apparatus according to claim 11 wherein said mixing means is a V-blender, a ribbon blender or a core blender.
17. The apparatus according to claim 16 wherein said detection means is a near infrared spectrophotometer, an ultraviolet spectrophotometer, a visible spectrophotometer, a Raman spectrophotometer, or a mid-range infrared spectrophotometer.
18. A method for mixing compositions of matter into a homogeneous mixture and detecting on-line the homogeneity of said mixture comprising:
(a) placing the compositions of matter to be mixed into a container of a mixing apparatus having an aperture;
(b) mixing the compositions of matter;
(c) detecting on-line the spectroscopic characteristic of the mixture during themixing process with a detection means for detecting on-line the homogeneity and potency of said mixture until the spectroscopic characteristic of said homogeneous mixture reaches a predetermined end point for homogeneity or until the spectroscopic characteristic converge.
(a) placing the compositions of matter to be mixed into a container of a mixing apparatus having an aperture;
(b) mixing the compositions of matter;
(c) detecting on-line the spectroscopic characteristic of the mixture during themixing process with a detection means for detecting on-line the homogeneity and potency of said mixture until the spectroscopic characteristic of said homogeneous mixture reaches a predetermined end point for homogeneity or until the spectroscopic characteristic converge.
19. The method according to claim 18 wherein said detecting on-line the spectroscopic characteristic of the mixture during the mixing process with said detection means is synchronized with the detecting of the rotational position of said container by a means for detecting rotational position.
20. The method according to claim 18 wherein said detection means comprises a spectroscopic means having an opening from which radiation emanates and is admitted and a conduction means for conducting radiation from said spectroscopic means to said mixture and conducting reflected or transflected radiation back to said spectroscopic means, said conduction means having a first end and asecond end and said conduction means connected to said spectroscopic means' opening at its first end and connected to said container's aperture at its second end.
21. The method according to claim 18 wherein said detection means comprises a spectroscopic means having an opening from which radiation emanates and reflected or transflected radiation from said mixture is admitted and said detection means' opening abuts said container's aperture.
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|---|---|---|---|
| US8523093A | 1993-06-29 | 1993-06-29 | |
| US08/085,230 | 1993-06-29 |
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| CA2126826A1 CA2126826A1 (en) | 1994-12-30 |
| CA2126826C true CA2126826C (en) | 1999-02-23 |
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| CA002126826A Expired - Fee Related CA2126826C (en) | 1993-06-29 | 1994-06-27 | Apparatus for mixing and detecting on-line homogeneity |
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| JP (1) | JP2650619B2 (en) |
| KR (1) | KR0162110B1 (en) |
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| US5504332A (en) * | 1994-08-26 | 1996-04-02 | Merck & Co., Inc. | Method and system for determining the homogeneity of tablets |
| EP0706040A1 (en) * | 1994-10-07 | 1996-04-10 | Bp Chemicals S.N.C. | Property determination |
| EP0706049A1 (en) * | 1994-10-07 | 1996-04-10 | Bp Chemicals S.N.C. | Cracking property determination |
| EP0706041A1 (en) * | 1994-10-07 | 1996-04-10 | Bp Chemicals S.N.C. | Chemicals property determination |
| EP0706050A1 (en) * | 1994-10-07 | 1996-04-10 | Bp Chemicals S.N.C. | Lubricant property determination |
| IT232075Y1 (en) * | 1994-10-11 | 1999-08-16 | Corob Srl | MIXER OF PRODUCTS GENERALLY LOCATED IN CONTAINERS AND SUPPORT AND CLAMPING GROUP FOR AT LEAST ONE OF SUCH CONTAINERS, |
| ATE262170T1 (en) * | 1996-04-09 | 2004-04-15 | Eutech Engineering Solutions L | PROCESS CONTROL |
| DE69636276T2 (en) * | 1996-04-09 | 2006-11-09 | Innovene Europe Ltd., Staines | Controlling a process |
| SE9802690D0 (en) | 1998-08-07 | 1998-08-07 | Astra Ab | Mixing apparatus |
| EP1265694B1 (en) | 2000-02-17 | 2004-07-21 | AstraZeneca UK Limited | Mixing apparatus and method |
| GB0003641D0 (en) * | 2000-02-17 | 2000-04-05 | Astrazeneca Uk Ltd | Mixing apparatus and method |
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-
1994
- 1994-06-03 AT AT94304010T patent/ATE157905T1/en not_active IP Right Cessation
- 1994-06-03 ES ES94304010T patent/ES2106449T3/en not_active Expired - Lifetime
- 1994-06-03 DK DK94304010.5T patent/DK0631810T3/en active
- 1994-06-03 EP EP94304010A patent/EP0631810B1/en not_active Expired - Lifetime
- 1994-06-03 DE DE69405483T patent/DE69405483T2/en not_active Expired - Fee Related
- 1994-06-23 JP JP6141356A patent/JP2650619B2/en not_active Expired - Fee Related
- 1994-06-27 CA CA002126826A patent/CA2126826C/en not_active Expired - Fee Related
- 1994-06-27 AU AU65997/94A patent/AU660875B2/en not_active Ceased
- 1994-06-28 KR KR1019940014952A patent/KR0162110B1/en not_active IP Right Cessation
- 1994-06-28 BR BR9402570A patent/BR9402570A/en not_active Application Discontinuation
- 1994-06-28 CN CN94107246A patent/CN1062490C/en not_active Expired - Fee Related
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1997
- 1997-10-22 GR GR970402775T patent/GR3025143T3/en unknown
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|---|---|
| ES2106449T3 (en) | 1997-11-01 |
| GR3025143T3 (en) | 1998-02-27 |
| DK0631810T3 (en) | 1997-10-20 |
| JPH0768146A (en) | 1995-03-14 |
| JP2650619B2 (en) | 1997-09-03 |
| KR950001299A (en) | 1995-01-03 |
| BR9402570A (en) | 1995-04-11 |
| EP0631810A1 (en) | 1995-01-04 |
| KR0162110B1 (en) | 1998-11-16 |
| ATE157905T1 (en) | 1997-09-15 |
| EP0631810B1 (en) | 1997-09-10 |
| CA2126826A1 (en) | 1994-12-30 |
| AU6599794A (en) | 1995-01-27 |
| DE69405483D1 (en) | 1997-10-16 |
| CN1100002A (en) | 1995-03-15 |
| DE69405483T2 (en) | 1998-01-15 |
| AU660875B2 (en) | 1995-07-06 |
| CN1062490C (en) | 2001-02-28 |
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| EEER | Examination request | ||
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