Abstract:
A dissolution sampling apparatus which automatically extracts aliquots which contain a dissolved drug in solution from a plurality of dissolution containing flasks and tests each aliquot for the amount of drug dissolved within the aliquot. The sampling apparatus can resupply the removed aliquot. back to its source or the aliquot can be discarded as waste with new media being resupplied to the source. A syringe is used to remove the aliquots. A mechanically operated valve could be used with each syringe or a plurality of solenoids instead of the mechanically operated valve.

Description:
REFERENCE TO PRIOR APPLICATION 
     The present application refers to provisional application No. 60/122,613 filed Mar. 3, 1999, by the same inventors and title. 
    
    
     BACKGROUND OF THE INVENTION 
     1) Field of the Invention 
     The field of this invention relates to dissolution testing equipment for determining the dissolving rate of drugs encapsulated in the form of a tablet, capsule or caplet, which are commonly known as pills and more particularly to an interfacing piece of equipment to be used as a dissolution sampling apparatus. 
     2) Description of the Prior Art 
     Drugs are commonly manufactured in the form of pills. The reason for using pills is that when the drug is swallowed by a human, the drug will be disseminated by the body over a period of time as the pill dissolves. Manufacturers of pills are required by law to determine the precise dissolving characteristics of their pill before it is placed on the market. In order to determine the dissolving characteristics, dissolution test equipment is utilized. Although dissolution test equipment is commonly used in conjunction with drugs designed for human consumption, it is considered to be within the scope of this invention to use it with other animals such as horses, cows, rabbits, cats, dogs, monkeys and so forth. 
     Every form of dissolution test equipment generally utilizes a plurality of liquid containing flasks called testing vessels. In each flask is to be placed a liquid called media, with this media essentially duplicating the liquid solution that is contained within the stomach of the human body. The precise quantity of the solution is placed within the flask. The pill is then inserted into the flask and the time of the insertion then noted. A mixing paddle is inserted within the flask with mixing at a precise rate then occurring. The mixing procedure is to duplicate the natural turbulence that is created within the stomach of the human. Aliquots are removed from the solution at precise time intervals with these aliquots then being analyzed to determine the amount of drug that has been dissolved within the solution in relation to the time that the pill has been in the solution. 
     In order to insure that the testing process is accomplished as accurate and quickly as possible, such dissolution testing apparatus, in the past, has been designed as follows: 
     1. Normally the dissolution testing apparatus would have six or eight flasks. Dissolution testing of the pill is accomplished simultaneously in all six or eight flasks with each flask to receive a pill. The average dissolving rate is then calculated between the flasks. 
     2. The flasks are placed in a bath with this bath to be maintained at a precise temperature. The temperature level is to essentially duplicate the temperature of the stomach liquid within the human. 
     In the past, the procedure in conjunction with the six or eight flasks is for the technician to remove the media from each individual flask and place it within a collecting vessel. A precise quantity of the media is to be removed and placed within the vessel. At times, it is then required to replace that precise same quantity of raw media back into the flask from which the media has been removed. Also, at other times the media that is being tested is to be reinserted back into the flask. Previously, this tedious procedure of removal of aliquots and replacement of the aliquots or media back into the flask has all been accomplished manually. Inherently, inaccuracies develop. Also because of the time it takes to complete the manual removal procedure, additional inaccuracies develop because what is being calculated is the amount of dissolution of drug within the media within a certain period of time and the removal and replacement procedure takes. time which affects the accuracy of the readings. 
     SUMMARY OF THE INVENTION 
     The dissolution sampling apparatus of the present invention is designed to automatically extract samples (aliquots) from multiple flasks that contain media and deposit these aliquots within collecting vials with each aliquot being deposited in a separate collecting vial. The sampling apparatus of this invention can also resupply the aliquot that has been removed back to the flask from which the sample has been taken or the sample can actually be discarded as waste. When discarded as waste, an additional quantity of the raw media liquid can be resupplied to the flask from which the sample has been taken. The present invention is to be used in conjunction with a dissolution test apparatus such is as shown and described within U.S. Pat. No. 5,639,974 which issued on Jun. 17, 1997. However, the present invention can be effectively interfaced with numerous other types of dissolution test apparatus and it is not intended to be solely used with the dissolution test apparatus of the aforementioned patent. However, all dissolution test apparatuses use a multitude, usually six to eight in number, of flasks with the media that is to be removed from each of these flasks. Within each flask is deposited a pill and the flask will normally include a mixing device which is to be used to create a turbulent action within each flask essentially duplicating the. turbulent action that is naturally created within the human stomach. The definition of pill is to also include capsules and caplets or any type of device which is to dissolve. 
     The present invention can comprise two different models with both models utilizing a plurality of piston operating devices which we refer to as syringes. There is to be a syringe for each vessel that contains media. Each syringe includes a body that is basically hollow within which is mounted a piston. This piston is retractable and expandable within the body. This retraction and expansion is accomplished by means of a motor which is precisely controlled by software. Associated with each syringe are a plurality of valves. Each valve is also operated by the software as to whether the valve is opened or closed. The first model is referred to as the DISSOSCAN and the-second model is referred to as the MAXIMIZER. The DISSOSCAN utilizes a single three-way solenoid valve that are mounted in conjunction with each syringe. The MAXIMIZER utilizes four two-way solenoid valves operated to accomplish the valving in conjunction with each syringe. The MAXIMIZER model is designed to be more versatile than the DISSOSCAN model with the MAXIMIZER able to perform a greater number of functions. However, the MAXIMIZER model has a disadvantage in that it is inherently more expensive. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     FIG. 1 is an enlarged cross-sectional view of the dual check valve that is used in conjunction with the DISSOSCAN model of dissolution sampling apparatus of the present invention showing the valve in the non-flow position; 
     FIG. 2 is a cross-sectional. view similar to FIG. 1 but showing the intake flow direction of the valve; 
     FIG. 3 is an enlarged view similar to FIG. 2 but showing the exit or outflow mode of direction of flow through the valve; 
     FIGS. 4-18 schematically show different modes of operation of the two models of dissolution test sampling aparatus of the present invention; and 
     FIG. 19 is an exterior view of the dissolution test apparatus of this invention. 
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     FIGS. 1-3 schematically show the dual check valve  72  that is utilized in conjunction with the DISSOSCAN model. The dual check valve  72  has an elongated housing  20  which includes an intake or second port  22  and an outlet or third port  24 . Separating the port  22  and the port  24  is a wall  26 . The wall  26  connects with a chamber  28 . Within the chamber  28  there is mounted a silicon disc which will be referred to as a diaphragm  30 . Connecting with the chamber  2 . 8  is a first port  32 . Port  32  is to be connected with a reservoir such as flask  34  shown in FIG.  4 . The-port  22  is connected through tube  36  to a syringe chamber  38  located within syringe body  40 . Movably mounted within the syringe chamber  38  is a piston  42 . Piston  42  is connected to rod  44  which in turn is mounted to an arm  46 . The arm  46  is mounted on lead screw  48 . The lead screw  48  is movable in the up direction as indicated by arrow  51  and down in the direction as indicated by arrow  50  by means of a motor  52 . 
     FIG. 1 is a representation of the actual construction of the valve  72  shown in FIGS. 1-3. The diaphragm  30  is shown in FIG. 1 closing of ports  24  and  32  so no media can pass through the valve  72 . Referring particularly to FIG. 2, when the piston  42  is moved in a retracted or down direction, which is in the direction of arrow  50 , media is caused to flow from the flask  34 , through tube  54 , through port  32 , around the silicon disc  30 , into port  22  and into the syringe chamber  38 . The direction of this flow is indicated by arrow  56 . When the desired precise quantity of media has been contained within the port  22  and syringe chamber  38 , the syringe motor  52  is activated which rotates the lead screw  48 .in an opposite direction which will be the up direction as shown by arrow  51 . This results in the piston  42  moving of the media contained within the chamber  38  and the port  22  to be pressed against the silicon disc  30  forcing the disc  30  tightly against seat  58 , which is clearly shown in FIG. 3 of the drawings. This permits the flow of media from port  22  directly into port  24 . This direction of flow is indicated by arrow  60 . This means that the media is to flow through tube  62  and then through a spectrophotometer  64 . Such spectrophotometers are well known in the field and function to immediately calculate the percentage of drug concentration within the liquid flowing through the spectrophotometer  64 . One manufacturer of spectrophotometers is Hewlett-Packard Corporation. 
     From the spectrophotometer  64  the liquid is to flow through tube  66  back into the flask  34 . FIG. 4 relates only to the DISSOSCAN model that can be utilized with only one bath  68  within which will normally be mounted somewhere in the range of six to eight of the flasks  34 . The bath  68  is to comprise a quantity of a liquid (usually water) that is maintained at a preset temperature. The flasks  34  are to be submerged in the bath  68  with the open top of the flasks  34  locate above the surface of the liquid in the bath  68  so none of the liquid can enter the flask  34 . The liquid in the bath  68  is to maintain the media in the flasks  34  at the preset temperature. For each flask  34  there is to be a separate syringe body  40  and piston  42 . The removal of the aliquots, or samples, from each of the flasks  34  is to be accomplished simultaneously with the flow through the spectrophotometer  64 . It is to be understood that the spectrophotometer  64  is deemed to be a conventional, commercially available apparatus which can be purchased from numerous sources not only from Hewlett-Packard Corporation. 
     Basically, the configuration shown in FIG. 4 utilizes one bath  68 , one sampling apparatus  70 , which includes multiple numbers of the syringe bodies  40  with their being a syringe body  40  for each flask  34  located within the bath  68 . There is utilized a detection apparatus in the form of a spectrophotometer  64  with the media that is removed from the flask  34  to be redeposited back into its same flask  34  from which it is removed. The media from the tube  36  is transmitted through the dual valve  72  which is the valve that was previously discussed in relation to FIGS. 1-3. Other types of valves could be used instead of the dual check valve  72 . One example is a 3-way solenoid valve. 
     Referring to FIG. 5, there is again shown the DISSOSCAN embodiment which utilizes one bath  68  and one sampling apparatus  70  with a multiple number of the syringe bodies  40  and pistons  42 . The difference in FIG. 5 when compared to FIG. 4 is that instead of returning the aliquot within the flask  34  by tube  62 , with it being understood there is a separate tube  62  for each syringe body  40 , the aliquots are deposited within a collector module  74 . The collector module  74  is deemed to be conventional and is commercially available as from Zymack Corporation of Hopkinton, Massachusetts. The collector module  74  includes a plurality of deposit vials  76 . Within each deposit vial  76  there is to be deposited an aliquot. One syringe body  40  connects with deposit vial  76  that is numbered  1  and  6 . Second syringe body  40  connects with a separate deposit vial  76  that is numbered  2  and so forth with each deposit vial  76  connecting with a separate syringe body  40 . The collector module  74  functions as an interim storage device to assemble and collate aliquots according to time collected with each deposit vial to then be removed and analyzed. The aliquot is then moved to a return vial  78 . Again, there is a return vial  78  for each deposit vial  76 . From the return vial  78  the aliquot is cause to flow through tube  80  back to be redeposited into its flask  34 . 
     Referring particularly to FIG. 6, there is again shown the DISSOSCAN embodiment with like numerals being employed to refer to like parts. The only difference between FIGS. 5 and 6 is that there is included within fluid conducting tube  62  a spectrophotometer  64 . The analyzed results from the aliquot collected in the collector module  74  can be used to compare with the results from the spectrophotometer  64 . 
     Reference now is to be had to FIGS. 7-18 which is directed to the different configurations of the MAXIMIZER embodiment of this invention. Again, similar numerals have been utilized to refer to similar parts. There again, is utilized at least the single bath  68  and a multitude of flasks  34 . For each flask  34  there is a separate syringe body  40  and a separate syringe piston  42 . Flow of media into and out of the syringe body  40  is now controlled by four separate solenoids  82 ,  84 ,  86  and  88  which are mounted on a solenoid housing. However, in the. configurations shown in FIGS. 7-9, the solenoids  84  and  86  are not operated. These solenoids  82 ,  84 ,  86  and  88  are controlled electronically by software which is supplied with the sampling apparatus of this invention. 
     Solenoid  88  controls the flow of media from flask  34  through tube  54  to syringe body  40 . Solenoid  82  controls the flow of media through outflow tube  62  to the spectrophotometer  64  and then hence through the tube  66  back to the flask  34 . The configuration in FIG. 7 is to detect the percentage of drug being dissolved within the media contained within each flask  34  by means of a spectrophotometer  64  which is similar to FIG.  4 . 
     Referring particularly to FIG. 8, there is shown a configuration wherein the media is supplied to a collector module  74 . Basically, the version shown in FIG. 8 will operate in a manner similar to FIG.  5 . 
     The configuration shown in FIG. 9 is basically similar to FIG. 8 with the addition of the spectrophotometer  64 . The configuration of FIG. 9 is basically similar to the configuration of FIG.  6 . 
     Referring particularly to FIG. 10, there is a MAXIMIZER configuration which is basically similar to that shown in FIG. 9 except that there is no collector module and there is utilized instead a waste flask  90 . Generally there will be only one waste flask  90  for all of the flasks  34 . Solenoid  84  is connected by tube  92  to a media replace flask  94 . Again, there will only be one media replace flask  94  for the series of flasks  34 . The user with the configuration of FIG. 10 has the option to load the syringes  40  with fresh media from flask  94  to replenish the flask  34 . If small volume aliquots are being taken, there may not be a need for a media replace flask. However, if large volume aliquots are being drawn, the volume of the media that remains after three or four aliquots are drawn is so low that saturation is approached of the remaining media in each flask by the dissolving pill. Saturation produces inaccurate results. To avoid saturation, a quantity of new media is introduced to the flask identical in volume to the aliquot immediately after its removal. Also, the media contained within flask  94  could be utilized to clean the tubes  62  and  66  as well as the internal chamber of the syringe  40  and deposit that within the waste flask  90 . Also, the solenoid  88  connects through tube  54  to probe  55 . When solenoid  88  is actuated, media is to be drawn within probe  55  and into tube  54  and into syringe chamber, 38 . 
     The configuration shown in FIG. 11 is basically similar to that shown in FIG. 10 with the exception that the tube  62  connects to collector module  74  and from vials  78  of module  74  the media is to be deposited within waste flask  90 . Replacement media in media replace flask  94  may be utilized as diluent and added to collected samples in collector  74  to achieve dilution. 
     The configuration shown in FIG. 12 is again for the MAXIMIZER and is the same as in FIG. 11 with the addition of the spectrophotometer  64  within the fluid conducting tube  62 . From the spectrophotometer  64  there is a fluid conducting tube  66  for each syringe body  40  each of which connects to a separate vial  76  of the collector module  74 . 
     Referring particular to FIG. 13 there is shown a configuration which is again basically similar to FIG. 12 except there is no collector module  74  and, instead of utilizing a single bath  68 , there is a second bath  96 . Included within the second bath  96  are a plurality of flasks  98 . It is to be understood that there will be a plurality of such flasks  98 , such as six or eight in number, in bath  96 . Each flask  98  is connected by valves  97  and  99  to a separate tube  100 . Valves  97  and  99  are similar to previously described valves  59  and  61 . From valve  97  there is a tube  120  that extends to directly adjacent the bottom of flasks  98  for withdrawing of media. Tube  122  extends from valve  99  to within flask  98  directly adjacent the top edge which is used to add media to flask  98 . Tube  100  is connected to solenoid  86 . As programmed by the user, a sampling sequence can be generated for each of the flasks  34  of the bath  68 . After that sampling sequence, there will be a second sampling sequence generated for each flask  98  of the bath  96 . Using of this configuration will decrease by half the time it takes to make the analyzations of the drug used in the flasks  98  is the same as in flasks  34  since twice as many aliquots are being withdrawn in the same time period. Also, flasks  98  could contain a different drug so the same apparatus could be used to make two different readings of two different drugs. Again, the user has the option to load the syringes with fresh media from flask  94  and replenish either flasks  34  or flasks  98 . Also, the fresh media could be utilized to wash the tubes  62  and  66  prior to being deposited within the waste-flask  90 . 
     The configuration shown in FIG. 14 is basically similar to FIG. 13 with the addition of the collector module  74  mounted in conjunction with the tubes  62 . From each vial  78  of the collector module  74 , the media is to be caused to flow through tubes  102  into waste flask  90 . There are similar tubes  102  in conjunction with the configurations of FIGS. 11 and 12. 
     FIG. 15 is basically similar to FIG. 14 with the addition of the spectrophotometer  64  within tube  62 . As programmed by the user, a flow cell flow signal is generated to the spectrophotometer  64 . A program sampling volume is then collected through tube  66  into the vial  76  of the collector module  74 . It is to be understood that the procedure is repeated for both baths  68  and  96 . The user has the option to load the syringes  40  with fresh media from flask  94  and then replenish lost media from either bath  34  or  98  or utilize the fresh media to wash the tubes prior to depositing of such within the waste flask  90 . 
     Referring particularly to FIG. 16, an additional bath  104  containing flasks  106  could be used. Valves  103  and  105  connect with tube  92  and solenoid  84 . Extending from valve  103  is a tube  124  that extends to directly adjacent the bottom of flask  106  to be used to withdraw media from flasks  106 . Extending from valve  105  is a tube  126  that extends just into flask  106  which is to be used to add media to flask  106 . Withdrawing media near the bottom of flasks  34 ,  98  and  106  is preferred so as to only withdraw media that contains the most dissolved drug. Adding media is preferred to occur near the top of flasks  34 ,  98  and  106  which is spaced from the bottom of the flasks and will normally affect the drug concentration in the flasks. Valves  103  and  105  are similar to valves  59  and  61 . Bath  104  could be added to, decrease the time by three that is required to. analyze a drug. Also, using bath  104  could permit three different drugs to be analyzed by the same apparatus. There will normally be the same number of flasks  106  to flasks  34 . In operation of the configuration shown in. FIG. 16, the user is to program the sequence to include the bath  106  in sequence with the other baths  96  and  68 . Tube  66  connects directly from the spectrophotometer  64  to the waste flask  90 . 
     FIG. 17 is a configuration which is again basically similar to FIG. 16 with the exception that instead of using the spectrophotometer  64  there is mounted the collector module  74  between the tubes  62  and  102 . 
     Referring particularly to the configuration shown in FIG. 18, the spectrophotometer  64  is placed within the tubes  62 . A program sampling volume is then collected into a collector module  74  after being analyzed by the spectrophotometer  64  for bath  68 . Before repeating the procedure on baths  96  and  104 , the MAXIMIZER waits for the offset time to elapse. Offset time is the inoperating time between collecting for bath  68  and bath  96 , and also bath  96  and bath  104 . No replacement media is available with this configuration. 
     Referring particularly to FIG. 19, there is shown an exterior housing  108  within which the MAXIMIZER embodiment could be located. Mounted on the housing  108  is an icon screen  110 . On the icon screen  110  are a plurality of icons  114 , numeral buttons  116  and mouse pad  118 . By the user physically contacting the appropriate icons  114  in the correct sequence, a certain program can be initiated within the MAXIMIZER embodiment of this invention. The housing  108  includes an on/off switch  109 .