Abstract:
A mixer supports a cradle holding an inlet component for a cascade impactor, and has sealing caps to close open ends of the component to trap a solvent in the component. The cradle is rotated by a motor for dissolving particles in the inlet component.

Description:
BACKGROUND OF THE INVENTION  
         [0001]    Two mixers are disclosed which are used for agitating solvents in components of dry powder inhalers to recover particles of internal clinging to wall of such components. The mixers are designed to assist laboratory personnel in the measurement of the size distribution of particulate matter emitted from metered-dose, dry-powder, and similar inhalers. Such inhalers are in common use for the treatment of asthma today and are increasingly important in the therapeutic delivery of pharmaceutical products of biotechnology.  
           [0002]    Inhalers must be tested regularly both during laboratory development of new products and for quality control and assurance for commercially sold products. The testing includes the measurement of the size distribution of particles emitted by the inhalers. The United States Pharmacopeia (USP) and similar British, European, and Japanese regulatory documents describe the use of cascade impaction devices as the acceptable method for measuring size distribution. Further, these international compendia describe the inlet that must be used to introduce the particles into the cascade impactor. This inlet is known commonly as the USP Induction Port and is shown on page 1902 of USP 24, Section 601.  
           [0003]    Because particulate matter accumulates in this induction port during each test of an inhaler device, the laboratory analyst doing the testing must quantify the mass of active drug material deposited in the induction port. Typically, this procedure involves washing the inside walls of the induction port with a solvent known to dissolve the active drug ingredient and in some manner insuring that all drug material is recovered from the inside walls of the induction port. The wash solvent is then analyzed, typically by high-performance liquid chromatography (HPLC), to quantify the drug material.  
           [0004]    The procedure of removing the drug material from the walls of the induction port is typically an ad hoc one with no assurance that all material is recovered. Further, the complete washing of the walls can consume a minimum of 50 ml of solvent and up to 200 ml of solvent. Consequently, the active drug compound is diluted with solvent, and the analysis via HPLC is relatively insensitive to the presence of the drug material, compromising the accuracy of the overall test.  
           [0005]    In addition, pre-separators are used in many impactors. Dry-powder inhalers typically contain large diluent particles along with the active drug material. These diluent particles would interfere with the functioning of the cascade impactor designed to recover the dry particles allowed to enter the impactor during a test. Consequently, when an analyst tests a DPI, a pre-separator is attached to the inlet of the cascade impactor. Some drug material accumulates in this pre-separator during testing, and the active drug material captured in the pre-separator must be quantified. This procedure requires washing with a known amount of solvent, typically 50 ml to 200 ml in prior art procedures, and/or shaking the device.  
         SUMMARY OF THE INVENTION  
         [0006]    The present invention relates to mixing devices that allow a user to add a minimum amount of solvent to parts that have recesses and bends, and to mix the solvent, while unattended, with the active drug material that has been clinging to the walls. This will thoroughly wash the walls, and cause the active drug material to be dissolved in the solvent. The handling of the solvent to recover the material of interest after this washing process is according to standards.  
           [0007]    The mixing devices of the present invention include fixtures that will hold the induction port, on the one hand, and a pre-separator on the other, and will rotate these components with the solvent contained in the chambers or passageways, after capping or sealing the openings, so the solvent acts on the material clinging to the interior surfaces.  
           [0008]    The mixing devices insure that all of the surface areas are contacted by the solvent during the mixing process, so that it is known that all of the active drug material has been dissolved and is available for analysis.  
           [0009]    The mixing devices are made so that they will permit use of a minimum amount of the solvent, and will yet provide adequate mixing to insure that all of the active drug materials are released. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0010]    [0010]FIG. 1 is a side elevational view of a mixing device utilized with a USP Induction Port;  
         [0011]    [0011]FIG. 2 is a first end elevational view thereof;  
         [0012]    [0012]FIG. 3 is a second end elevational view thereof;  
         [0013]    [0013]FIG. 4 is a side elevational view of a second mixing device adapted specifically for a pre-separator, for holding it in place for agitation;  
         [0014]    [0014]FIG. 5 is a side elevational view showing the mixing stand in position; and  
         [0015]    [0015]FIG. 6 is a schematic sectional view taken on line  6 - 6  in FIG. 4. 
     
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS  
       [0016]    Referring to FIG. 1, a stand or frame  10  is used as a frame for the mixing device indicated generally at  12 . The stand has a base  14 , and a pair of upright end members  16  and  18 . The upright end members support bearings  20 A and  20 B, that in turn rotatably mount shaft portions  22 A and  22 B that are used for supporting a cradle  24 . The cradle  24  has a base  26 , and end supports  28  and  30  fixed to the base end supports, as shown, have bent wall portions  28 A and  30 A that are formed at a substantially  450  to the main portions of the end supports. These bent wall portions have threaded openings to support threaded rods  32 A and  32 B. The threaded rods have handles  34 A and  34 B for rotating them manually, and in addition, each of the rods  32 A and  32 B holds a cap or cup structure  36 A and  36 B which are on the inner sides of the bent wall portions  28 A and  30 A, and are positioned between the end supports  28  and  30 .  
         [0017]    A USP Induction Port is indicated at  40 , and it has two tubular sections  42  and  44 , at right angles to each other in a fixed assembly. The tubular sections  42  and  44  have standard open end connections or couplings shown at  42 A and  44 A. The tubular sections form a passageway through the interiors. In order to support the induction port  40  in the cradle  24 , the screws  32 A and  32 B are backed out, so that the cup members  36 A and  36 B will permit the USP Inlet Port to slip into place, and then the screws are threaded down so that the cup members  36 A and  36 B cover the open ends of the couplings  42 A and  44 A. Prior to putting the inlet in position, and closing it off, a suitable amount of solvent is added to the interior chamber.  
         [0018]    The cradle is then rotatably driven, by driving it with a motor  46  that can be operated through a computer control  48  as to the timing, speed, and the amount of rotation. Pneumatic motors could be used, but a stepper motor is shown as an exemplary embodiment.  
         [0019]    The USP inlet will rotate around, and the solvent that is retained inside the tube will flow back and forth as the unit is rotated, and will contact all of the interior surfaces of the tubular sections  42  and  44 .  
         [0020]    In operation, the USP Inlet  40  is charged with a minimum amount of solvent, generally approximately 10 ml to 20 ml, and then the unit is put into place and the screws  32 A and  32 B are threaded so the caps  36 A and  36 B hold the inlet between the caps and seal the end openings.  
         [0021]    The entire inlet and cradle assembly then is rotated, and the solvent will slosh or flow back and forth between both ends and the center portion  50  of the inlet, to insure adequate passage of the solvent over the surfaces to dissolve the particles of the active drug material.  
         [0022]    Because the rotation is done by machine, the user not only saves time, because he can be at other tasks during the time that it is being used, but he avoids the tedium of having to shake the inlet port himself and to look into it to see if all the drug material has been recovered. Typically, the device can be rotated continuously or in one direction, or can be moved back and forth about the axis of the shafts  22 A and  22 B.  
         [0023]    A second mixer is shown in FIGS. 4 through 6, and in this instance, a pre-separator assembly  60  is being cleaned. It has an interior chamber, shown fragmentarily at  62 , an inlet  64 , and an outlet tube  66 . In some of these pre-separators, there is an impaction plate in the center portions that is shown schematically at  68 , but in any event the use is with the flow of an aerosol through the inlet  64 , and the interior chamber  62  to the outlet  66 .  
         [0024]    The fixture of the present invention includes a frame  69  that has a base  69 A supporting upright members  70 A and  70 B, that in turn rotatably mount a cradle  72 . The cradle  72  has shafts  74 A and  74 B that are rotatably mounted on suitable bearings on the upright members  70 A and  70 B of the frame  69 .  
         [0025]    The cradle  72  has a lower support cross member  76 , and an upper cross member  78  joining side members  77 A and  77 B. These cross members support hold cups for holding the pre-separator  60 . The lower cross member  76  has an upwardly facing cup  80  that will receive the end of the outlet  66 , as shown. This cup  80  is supported on the cross member  76  and has a shaft  81  that rotates in a bearing in the cross member  76 . A turnstile drive member  82  is driven by the lower end of shaft  81  that has four arms that protrude at 90° to each other. Two of the arms  82 A and  82 B are shown in FIG. 4, and two of the arms  82 C and  82 D are shown in FIG. 5. The cup  80  is rotatably mounted in the bearing  84  so that the cup will freely rotate.  
         [0026]    An upright post  86  is fixed to the lower frame member  68 A and extends upwardly. This post  68  acts as a turnstile, as will be explained.  
         [0027]    The upper cross member  78  rotatably supports a screw threaded shaft  88  that threads through a nut  89  that is mounted in a bearing  90  so the screw threaded shaft can rotate and also can be threadably adjusted. In other words, the bearing hub will permit the nut and shaft to rotate, but the screw threaded shaft  88  can be threaded, to move the cap shown at  92  vertically toward and away from the pre-separator housing  60 .  
         [0028]    In use, the device can be driven with a suitable motor  96  that is driven from a computer  98  in a normal manner. This too can be a stepper motor or could be a pneumatic rotary actuator as desired. It also could be a reversible DC motor.  
         [0029]    The screw threaded shaft  88  has a manual handle  88 A, can be threaded toward and away from the cross member  78 .  
         [0030]    When the pre-separator  60  is to be cleaned with a solvent, it is placed with the outlet  66  in the lower cup  80 , and then solvent is put into the inlet  64 , again using a limited amount of the solvent, probably in the range of 30-40 ml. Then the cup  92  is lowered into position to hold the pre-separator in a sealed position. Suitable gasketing materials can be used in the cups in this form of the invention, as well as the other form of the invention, to insure no leakage.  
         [0031]    Once the pre-separator  60  is held between the cups  80  and  92 , the motor  96  can be started and the unit can be rotated 360° about the shafts  74 A and  74 B. As it rotates, the post  84  will engage one of the arms  82 A- 82 D and will rotate the pre-separator  60  about the upright axis, that is indicated at  100 .  
         [0032]    In this way, the pre-separator is indexed 90° about the upright axis for each revolution about the horizontal axis. If desired the pre-separator can be rotated a selected number of degrees and then rotated in a reverse direction for proper use of the solvent in dissolving the drug particles of interest.  
         [0033]    The rotation about the vertical axis caused by the turnstile type post and cross member, insures that there are no dead zones inside the pre-separator that remain unwashed or untouched by the solvent. The user can also reverse the direction of the rotation about the horizontal axis to effect complete mixing.  
         [0034]    The mixing devices shown improve the repeatability and uniformity of the sample recovery process from the pre-separator and from the USP Induction Port.  
         [0035]    Although the present invention has been described with reference to preferred embodiments, workers skilled in the art will recognize that changes may be made in form and detail without departing from the spirit and scope of the invention.