Patent Publication Number: US-2003235108-A1

Title: Method and apparatus for detecting on-line homogeneity

Description:
FIELD OF THE PRESENT INVENTION  
       [0001] The present invention relates generally to spectroscopy systems. More particularly, the invention relates to a method and apparatus for detecting on-line the homogeneity and constituent concentration of compositions of matter.  
       BACKGROUND OF THE INVENTION  
       [0002] A critical step in the preparation of a pharmaceutical compositions, which often comprises five (5) or more constituents, including the active drug(s), is mixing or blending. Indeed, it is imperative that the pharmaceutical composition is homogenous to ensure that the appropriate dosage of the active drug(s) is delivered to a recipient.  
       [0003] The homogeneity and, of course, constituent concentration of pharmaceutical compositions are thus critical factors that are closely monitored during processing. Various conventional methods have been employed to determine the homogeneity and constituent concentration of pharmaceutical compositions. Most of the conventional methods are, however, complex and time consuming.  
       [0004] The conventional methods typically involve stopping the blender and removing nine (9) or more samples from various locations in the blender. The samples are then taken to a laboratory and analyzed. The blender remains shut down while the samples are analyzed, which can take from 24 to 48 hours to complete.  
       [0005] Another time consuming aspect of the traditional methods is the hit or miss approach to determine when the mixture is homogeneous. Typically, the blender is run for a pre-determined amount of time. The blender is then stopped and the samples are removed and analyzed. If the mixture is not homogenous, the blender is run again and the testing procedure is repeated.  
       [0006] Further, the mixture may reach homogeneity at a time-point before the pre-determined 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 constituents (or components).  
       [0007] In U.S. Pat. No. 5,946,088 a further method of determining the homogeneity and drug concentration (i.e., potentency) of pharmaceutical compositions is disclosed. The method involves the use of a modified “V”-blender having spectroscopic detection means disposed proximate the axis of rotation. The “V”-blender is adapted to provide “on-line” spectroscopic characteristics as the “V”-blender is rotated.  
       [0008] Although the method disclosed in the &#39;088 patent overcomes several of the above noted drawbacks associated with conventional methods of determining homogeneity and constituent concentration of pharmaceutical compositions, the method has several significant limitations. First, the method merely employs one (1) transflectance probe and is inherently limited to a maximum of two (2) probes. Second, the method is limited to a “V”-blender or the like.  
       [0009] It is therefore an object of the present invention to provide a method and apparatus for detecting on-line homogeneity and constituent concentration of pharmaceutical compositions that is readily adaptable to virtually all conventional blenders.  
       [0010] It is another object of the invention to provide a method and apparatus for detecting on-line homogeneity and constituent concentration of pharmaceutical compositions that employs a plurality of spectroscopic detection means at various positions on the blender.  
       [0011] It is yet another object of the invention to provide method and apparatus for detecting on-line homogeneity and constituent concentration of pharmaceutical compositions that includes control means to eliminate over mixing of the pharmaceutical composition.  
       SUMMARY OF THE INVENTION  
       [0012] In accordance with the above objects and those that will be mentioned and will become apparent below, the method and apparatus for detecting on-line the homogeneity and constituent concentration of compositions of matter in accordance with this invention comprises mixing means for mixing the compositions of matter; and spectroscopic means for detecting on-line the homogeneity and constituent concentration of the compositions of matter, the spectroscopic means including a plurality of spectroscopic detection means disposed on the mixing means for providing light to the compositions of matter and detecting emission light from the compositions of matter, first control means for providing the light to the plurality of spectroscopic detection means and analyzing the emission light from the plurality of spectroscopic detection means, and second control means in communication with the first control means and the plurality of spectroscopic detection means for controlling the transmission of the light from the first control means to the plurality of spectroscopic detection means and the emission light from the plurality of spectroscopic detection means to the first control means, the second control means including switch means for connecting a respective one of the plurality of spectroscopic detection means to the first control means. 
     
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
     [0013] Further features and advantages will become apparent from the following and more particular description of the preferred embodiments of the invention, as illustrated in the accompanying drawings, and in which like referenced characters generally refer to the same parts or elements throughout the views, and in which:  
     [0014]FIG. 1 is a perspective view of a prior art tote blending system;  
     [0015]FIG. 2 is a partial section perspective view of a prior art mixing tote;  
     [0016]FIG. 3 is a perspective schematic illustration of the prior art mixing tote shown in FIG. 2;  
     [0017] FIGS.  4 - 6  are partial section perspective views of the mixing tote shown in FIG. 2, illustrating the detection means according to the invention;  
     [0018]FIG. 7 is a perspective view of a first embodiment of the invention;  
     [0019]FIG. 8 is a perspective view of the second control means according to the invention;  
     [0020]FIG. 9 is a partial section perspective view of the drive axle assembly according to the invention;  
     [0021]FIG. 10 is a further perspective view of the first embodiment of the invention shown in FIG. 7, illustrating the system enclosure according to the invention;  
     [0022]FIG. 11 is a partial section perspective view of the mixing tote shown in FIG. 2, illustrating the remote detection means according to the invention; and  
     [0023]FIG. 12 is a perspective view of a second embodiment of the invention, incorporating the remote detection means shown in FIG. 11. 
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT  
     [0024] The present invention substantially reduces or eliminates the disadvantages and drawbacks associated with prior art methods of determining homogeneity and constituent concentration of compositions of matter. As discussed in detail below, the invention provides a novel means for “on-line” determination of homogeneity and constituent concentration of compositions of matter and, in particular, pharmaceutical compositions at a plurality of positions in a mixing container or tote. The noted data may further be provided in a random manner or over a pre-determined time sequence.  
     [0025] Different types of blenders or blending systems are currently used in the art for blending or mixing pharmaceutical compositions, such as a V-blender, core blender and ribbon blender. Illustrative is the blenders disclosed in U.S. Pat. Nos. 5,946,088 and 590,441, which are incorporated by reference herein.  
     [0026] A further blending system is the “tote blending” system distributed by Matcon USA, Inc., Sewall, N.J., which is incorporated by reference herein. As discussed in detail below, the blending system  5  mixes compositions of matter, such as powders or liquids, by rotating a “blending tote”  10  containing the composition of matter about an axis of rotation. The tote  10 , illustrated in FIGS. 2 and 3, typically has a height (H) in the range of 55″ in. to 65″ in. and is adapted to hold approximately 1586 liters of matter.  
     [0027] Referring to FIG. 2, the blending tote  10  includes a substantially rectangular section  12  and a substantially tapered section  14  disposed on the bottom end thereof. The tote  10  also includes a first opening  11   a  at the top of the tote  10  that is generally employed to charge the tote  10  with the individual compositions of matter that are to be mixed (or blended) and a second opening  11   b  at the bottom of the tote  10  that is generally employed to discharge the mixed, homogeneous composition. Openings  11   a,    11   b  are covered and sealed during the mixing process by conventional butterfly  13  or cone valves.  
     [0028] The tote  10  further includes a plurality of corner posts  16  adapted to removeably engage the mixer clamping frame  18 . As illustrated in FIG. 2, a respective post  16  is disposed at each top corner of the tote rectangular section  12 .  
     [0029] Referring to FIGS. 1 and 3, the tote  10  is positioned in the mixer cage  22  such that the line that intersects points (or corners) A and B, designated L 1 , or the line that intersects points C and D, designated L 2 , is substantially coincident the rotational axis, RA, of the tote  10 . As will be appreciated by one having ordinary skill in the art, the noted position of the tote  10  during rotation provides optimal blending of the matter contained therein. Thus, the tote blending system illustrated in FIG. 1 is the preferred blending means of the invention. However, as will also be appreciated by one having ordinary skill in the art, the method and apparatus of the invention, discussed in detail below, is also readily adaptable to the conventional blenders identified above.  
     [0030] Referring back to FIG. 1, the tote  10  is secured in the cage  22  of the mixer  20  via the engagement of the linearly moveable clamping frame  18  and the tote corner posts  16 . As illustrated in FIG. 1, the cage  22  is rotatably connected to the mixer support housing  23  via a conventional axle assembly  25  and the control housing  24  via a conventional “drive” axle assembly  26 . The cage  22  and, hence, tote  10  is rotated about axis RA via conventional drive means  21  that is operatively connected to the drive axle assembly  26  (See FIG. 7).  
     [0031] As will be appreciated by one having ordinary skill in the art, various conventional “rotation means”, such as the noted axle assemblies  25 ,  26 , may be employed within the scope of the invention to facilitate rotatable connection of the cage  22  to the housings  23 , 24 . The conventional rotation means may also be employed with the additional mixing means identified above.  
     [0032] As further illustrated in FIG. 1, the blending system  5  typically comprises an open, stand-alone system. However, as illustrated in FIG. 10, the blending system  5  may include an enclosure  6  to meet stringent safety and quality control requirements.  
     [0033] As indicated above, a key feature of the present invention is the spectroscopic means. In a preferred embodiment of the invention, the spectroscopic means includes a plurality of spectroscopic detection means to determine the homogeneity and constituent concentration of the pharmaceutical composition during the mixing operation (i.e., on-line). By the term “spectroscopic detection means”, as used herein, it is meant to mean and include a reflectance probe, transflectance probe, near-infrared spectrophotometer, ultraviolet spectrophotometer, mid-range infrared spectrophotometer, visible spectrophotometer, fluorescence spectrophotometer and Raman spectrophotometer.  
     [0034] Referring now to FIG. 7, according to the invention, the spectroscopic means  30  of the invention further includes (i) first control means  34  having light source means  34   a  for providing the desired wavelength of light (or radiation) to the spectroscopic detection means  32  and analyzer means  34   b  for analyzing the emission light detected by the spectroscopic detection means  32 , and (ii) second control means  36  having a plurality of optic lead inputs  38  and switch means adapted to selectively facilitate communication by and between the primary optic lead  40  and a selective one of the optic lead inputs  38  (See FIGS. 8 and 9). Carl Zeiss, which are incorporated by reference herein. The analyzer means  34   b  may also comprise a personal computer.  
     [0035] As illustrated in FIGS.  7 - 9 , the spectroscopic means  30  further includes (i) at least one detection means lead  42 , having conduction means for conducting light, (ii) a first control lead  46  that is operatively connected to the control panel  48  and the first control means  34 , and (iii) a second control lead  44  that is operatively connected to the first and second control means  34 ,  36  to facilitate transmission of at least a first control signal from the second control means  36  to the first control means  34  indicative of the location of a respective one of the spectroscopic detection means  32  that is in communication with the first control means  34  (via the second control means switch means), a second control signal from the first control means  34  to the second control means  36  to control the conduction of the light from the light source means  34   a  to a respective one of the spectroscopic detection means  32 , and a third control signal for controlling the conduction of emission light from a respective one of the spectroscopic detection means  32  to the analyzer means  34   b.    
     [0036] According to the invention, the first control means  34  is preferably disposed in the control housing  24 . The second control means  36  is preferably mounted to the mixer cage  22  (See FIG. 7).  
     [0037] Referring now to FIG. 9, to facilitate communication by and between the first and second control means  34 ,  36 , the drive axle assembly  26  (i.e., rotation means) includes a first (or outer) member  50  adapted to rotate with the cage  22  and, hence, mixing tote  10  and a second (or inner) member  52  adapted to remain relatively fixed in relation to the first member  50  during rotation of the cage  22 . In a preferred embodiment of the invention, the second member  52  comprises a rotatable sleeve assembly.  
     [0038] As illustrated in FIG. 9, the sleeve assembly  52  includes a substantially lateral communication port  54  adapted to receive the primary optic lead  40  and second control lead  44 . Thus, during rotation of the first member  50 , the sleeve assembly  52  remains relatively fixed to eliminate “kinking” of the leads  40 ,  44 .  
     [0039] As will be appreciated by one having ordinary skill in the art, various conventional rotation means having at least two rotatable members may be employed within the scope of the invention to facilitate rotation of one member in communication with the cage  22  (or other mixer/blender) relative to a second member that receives the leads  40 , 44  and remains relatively fixed during rotation of the first member. Such rotation means includes a conventional bearing assembly and bushing assembly.  
     [0040] Referring now to FIG. 4, there is shown one embodiment of the invention wherein two (2) spectroscopic detection means  32  are employed. The spectroscopic detection means  32  are preferably disposed proximate the bottom of the mixing tote  10 .  
     [0041] However, as indicated, a plurality of spectroscopic detection means  32  disposed at various positions, such as that illustrated in FIGS. 5 and 6, may be employed within the scope of the invention. In a preferred embodiment, at least ten (10) spectroscopic detection means  30  are employed (See, e.g., FIG. 6).  
     [0042] As illustrated in FIG. 7, each of the spectroscopic detection means  32  shown in FIG. 4 is operatively connected to the second control means  36  via detection means leads  42 . As indicated above, each lead  42  includes conduction means, such as a light pipe, optics and fiber optic bundle. In a preferred embodiment of the invention, the conduction means comprises a fiber optic bundle having two sets of optical fibers; a first set of optical fibers to convey light from the first control means  34  (i.e., light source means  34   a ) to the spectroscopic detection means  32  and, hence, mixture inside the mixing tote  10  and a second set of optical fibers to convey the detected (i.e., emission) light back to the first control means  34  (i.e., analyzer means  34   b ).  
     [0043] As indicated above, various spectroscopic detection means  32  may be employed within the scope of the invention. In a preferred embodiment, the spectroscopic detection means  32  comprises a reflectance probe. A typical reflectance probe is disclosed in U.S. Pat. No. 5,044,755, which is incorporated by reference herein.  
     [0044] In the noted reflectance probe, a lens collimates the light emerging from the fiber optic bundle. The optic ray is then guided through a sample cell and reflected back to the same lens that focuses the light into the same fiber optic bundle.  
     [0045] According to the invention, the mixing and detection process of the invention comprises the following: The mixing tote  10  charged with the pharmaceutical composition is initially loaded into the mixer  20  and secured therein by the clamping frame  18 . The detection means leads  42  are then connected to each detection means  32  (i.e., reflectance probe) and a respective optic lead input  38  of the second control means  36 .  
     [0046] The location of each detection means lead  42  on the second control means  36  (i.e., optic lead input  38 ), the corresponding location of a respective one of the spectroscopic detection means  32 , and the desired spectroscopic scanning sequence are entered into the system  5  via the control panel  48 . Further information, such as mix time and/or sequence, and desired homogeneity and concentration levels, may also be inputted into the system  5  via the control panel  48 . The noted information is then communicated to the first control means  34  via first control lead  46 .  
     [0047] The mixing tote  10  is then rotated by the mixer  20  (See FIG. 10) and the desired spectroscopic data (e.g., absorption spectrum) is acquired by the spectroscopic means  30  pursuant to the inputted spectroscopic scanning sequence. As discussed above, the spectroscopic data is then communicated to the analyzer means  34   b  where the homogeneity and constituent concentration of the pharmaceutical composition is determined by conventional means.  
     [0048] According to the invention, the tote  10  is rotated for either a pre-determined period of time or until the pharmaceutical composition contained in the tote  10  reaches a desired level of homogeneity. The desired homogeneity level may be either the average of the spectroscopic data detected by all detection means  32  or the minimum value detected by each detection means  32 .  
     [0049] As illustrated in FIG. 7, the control panel  48  further includes display means  49  adapted to visually display a variety of parameters, including the homogeneity and/or constituent concentration of the pharmaceutical composition proximate each spectroscopic detection means  32  during virtually any point in the mixing process. The display means  49  are further adapted to visually display other pertinent information, such as the heat or batch number, operator identification, etc..  
     [0050] Referring now to FIG. 11, there is shown an additional embodiment of the invention. In the noted embodiment, a plurality of spectroscopic detection means  32  are similarly employed. However, as illustrated in FIG. 11, each spectroscopic detection means  32  includes intergral control means  60 . According to the invention, the control means  60  similarly includes light source means for providing the desired wavelength of light to the detection means  32  and analyzer means for analyzing the emission light detected by the spectroscopic detection means  32 .  
     [0051] The control means  60  further includes means for remotely transmitting at least a first detection signal indicative of the spectroscopic characteristics of the pharmaceutical composition contained in the tote  10  and receiving at least a first control signal from the control panel  70 . According to the invention, the means for transmitting and receiving the first detection signal and first control signal can comprise a radio frequency (RF) transmitter/receiver, an infrared transmitter/receiver and a low power microwave transmitter/receiver. In a preferred embodiment of the invention, the means for transmitting and receiving the noted signals comprises a RF transmitter/receiver  62 .  
     [0052] According to the invention, the control panel  70  also includes a RF transmitter/receiver  72 . The RF transmitter/receiver  72  is adapted to receive the first detection signal from each respective control means  62  and transmit the first control signal to each of the control means  62 .  
     [0053] Referring now to FIG. 12, the control panel  70  is preferably mounted to the mixing housing  24 . The control panel  70  also includes display means  74  that is capable of visually displaying the same information discussed above.  
     [0054] Operation of the spectroscopic system illustrated in FIGS. 11 and 12 is also quite similar to the operation of the above-discussed embodiment. However, in this instance, the spectroscopic characteristics are directly communicated to the display means  74  via RF signals. The second control means  36  and leads  40 ,  42 ,  44  discussed above are thus eliminated.  
     SUMMARY  
     [0055] From the foregoing description, one of ordinary skill in the art can easily ascertain that the present invention provides novel means for accurate, cost efficient, on-line detection of homogeneity and concentration of pharmaceutical compositions that is readily adaptable to virtually all conventional blenders and blending systems.  
     [0056] Without departing from the spirit and scope of this invention, one of ordinary skill can make various changes and modifications to the invention to adapt it to various usage and conditions. As such, these changes and modifications are properly, equitably, and intended to be, within the full range of equivalence of the following claims.