Abstract:
An automated synthesizer is disclosed in which the reaction wells are moved by a carousel into alignment with stationary nozzles that are in communication with the source of reactants and/or washing solutions. By moving the wells rather than moving the nozzles for the delivery of reagents and washing solutions, the amount of time required to introduce reagent is substantially reduced.

Description:
[0001]     This application claims the benefit of the filing date of provisional application Ser. No. 60/735,276, entitled AUTOMATED ROTARY SYNTHESIZER which application is incorporated by reference herein. 
     
    
     FIELD OF THE INVENTION  
       [0002]     This invention relates to automated chemical synthesizers and more particularly to improved automated rotary chemical synthesizer.  
       BACKGROUND OF THE INVENTION  
       [0003]     The production of chemicals and biochemicals and products such as, for example, peptides, proteins, carbohydrates and DNA and genetic material has been simplified with the advent of synthesizers which automatically or semi-automatically carry out the stepwise addition of reagents and carry out reactions, such as the synthesis of peptides, or for carrying out fragment coupling reactions. Conventionally, fully automated synthesizers include a robotic arm that carries a vertically moveable probe for travel between a source of reagents and individual reaction wells in which the reaction occurs.  
         [0004]     The automated synthesizers relying on robotic arms to transfer reagents exhibit several deficiencies. One deficiency is that the robotic arm moves slowly and must make a large number of moves, depending on the number of reactants in the finished product, between the source of reagent, wash solution and the reaction wells thus requiring a substantial amount of time for reagent delivery, particularly when carrying out a large number of reactions in a single block. The use of a single probe on the robotic arm can result in contamination as the probe handles more than one reagent. In addition such synthesizers can require a high level of maintenance to insure the correct calibration of the robotic arm to insure precise alignment with each reaction well. Conventional synthesizers rely on an agitator for mixing of the reagents in the reaction wells. This agitation coupled with the conventional configuration of the reaction wells can result in splash out of material and contamination between adjacent wells of the block.  
       SUMMARY OF THE INVENTION  
       [0005]     According to the present invention improved automated synthesizers are provided in which reagents are delivered to reaction wells precisely and at a faster rate than for the synthesizers that utilize a robotic arm. The automated synthesizer of the invention is reliable and economical. In addition, cross-contamination is essentially eliminated as the injection nozzle does not travel in horizontal and vertical directions over a reaction well as is the case for synthesizers employing a robotic arm. Reagents are dispensed directly into the reaction well from containers and dispensing nozzles that are dedicated to a single reagent so the fluid path for each reagent does not come into contact with any other reagent, eliminating another area of contamination.  
         [0006]     In accordance with the present invention, there is provided an improved automated synthesizer in which the reaction wells are moved into alignment with stationary nozzles that are in communication with the source of reactants and/or washing solutions. By moving the wells rather than moving the nozzles for the delivery of reagents and washing solutions, the amount of time required to introduce reagent is substantially reduced. The number of washing steps required is reduced since a single dispensing nozzle delivers only one reagent so that a washing step is eliminated when a different reagent is to be delivered to a reaction well. The danger of cross-contamination due to the movement of a dispensing nozzle over the reaction block that can give rise to the possibility of small amounts of reagent from the nozzle gaining access into other reaction wells. Also contamination is eliminated since a separate injector nozzle dispenses one reagent only. In addition, the agitation of the reaction block is eliminated and improved mixing of reactants is achieved by the configuration of the reaction wells and by the movement of the reaction wells as they are brought into alignment with a reagent nozzle or a wash fluid nozzle.  
         [0007]     More particularly, in one embodiment the automated synthesizer comprises a rotatable carousel having at least one reaction well disposed at the periphery of the rotatable carousel. A reaction well includes a reaction chamber and an injection port. Preferably a reaction well includes an access port for an inert gas and a drain port for emptying the well. Rotation of the carousel brings at least one of the reaction wells into alignment with a dispensing nozzle of a stationary delivery system for delivery of reagent into the reaction chamber of the reaction well. A reversible stepper motor powers the rotatable carousel for rotation in either direction.  
         [0008]     In a preferred embodiment the stationary delivery system comprises at least one reagent station comprising a container for reactants and a dispensing nozzle that is in fluid communication with the reactant in the container. In one embodiment a syringe is activated to draw reagent from the container and to dispense a controlled amount of reagent through the dispensing nozzle into the reaction chamber. A stationary wash station and drain system includes a plurality of wash injectors that are in fluid communication with one or more wash fluids. One or more linear activators are provided to lower the wash nozzles into the reaction wells for an essentially pressure tight seal and to raise the nozzle for clearance during rotation of the carousel. A frame member in the housing supports the reactant containers and wash fluid containers. While the invention is described herein in connection with a syringe and plunger it should be understood that other commercially available alternative injection systems can be employed with good results. For example, the confluent pump and valve module distributed by Sapphire Engineering, Pocasset Mass. can be used with equal results.  
         [0009]     A control system including a CPU, keyboard and monitor are provided for programming and controlling the sequence of reactions and washing steps carried out by the automated synthesizer. Pulses of nitrogen gas are introduced into the reaction chamber to purge the liquid portion out of the container through the drain port for disposal or for collection. The drain port includes a suitable device to maintain solids such as solid support resins in the reaction chamber. Such a device may include a filter, a mechanical valve (check, duckbill or pinch) with set cracking pressure, an electronically controlled solenoid valve, or a vertical trap.  
         [0010]     In one embodiment of the invention, the stationary delivery system includes one or more removable cartridges that contain reactant and other liquids required for the reaction. A dispensing nozzle is also associated with the cartridge so that each cartridge of the delivery system is self-contained. In yet another embodiment of the invention, a suitable sensor is provided to indicate the level of reactant in the cartridge.  
         [0011]     The embodiments of the invention described herein have found utility in peptide formation and other solid phase and liquid phase chemical reactions can be performed using the synthesizer of the present invention. 
     
    
     DESCRIPTION OF THE DRAWINGS  
       [0012]      FIG. 1  is a schematic diagram of an automated synthesizer designed in accordance with the present invention;  
         [0013]      FIG. 2  is a perspective view of one embodiment of the invention;  
         [0014]      FIG. 3  illustrates portion of the carousel platform carrying the reaction wells;  
         [0015]      FIG. 4  illustrates the carousel platform support and drive system;  
         [0016]      FIG. 5  is an exploded view of a segment of the carousel showing reaction cavities and reaction wells;  
         [0017]      FIG. 6  is a side sectional view of a reaction well;  
         [0018]      FIG. 7  is a perspective view of the reagent delivery and wash stations of the synthesizer of the invention;  
         [0019]      FIG. 8  is a top plan view of an embodiment of the invention showing six reagent or wash fluid delivery stations;  
         [0020]      FIG. 9  is a side sectional view of a station for delivery of reagent or wash fluid to a reaction well;  
         [0021]      FIG. 10  illustrates the front elevation of a cartridge adapted for use at a wash station;  
         [0022]      FIG. 11  is a side elevation of the cartridge of  FIG. 10 ;  
         [0023]      FIG. 12  is a side sectional view of another embodiment of a reaction well;  
         [0024]      FIG. 13A  is a top plan view of the carousel showing reaction wells oriented with their long dimensions normal to the carousel axis of rotation;  
         [0025]      FIG. 13B  is a top plan view of the carousel showing reaction wells oriented with their long dimensions disposed at an angle to the carousel axis of rotation; and  
         [0026]      FIG. 14  is a sectional view, partially broken away for compactness of illustration, showing a collection vessel and its attachment to a carousel. 
     
    
     DESCRIPTION OF THE INVENTION  
       [0027]     Referring to  FIG. 1  there is illustrated in schematic form an automated chemical synthesizer in accordance with the present invention. A rotatable carousel  10  carrying reaction wells  12  is drivingly engaged to a drive motor  14  for moving at least one of the reaction wells into alignment with a stationary reagent delivery station, shown generally as  20 . The reagent delivery station includes a fluid pump  22  that is in fluid communication with a reservoir  24  and a dispensing nozzle  26 . Valves  28  are provided to insure one-way flow from the reservoir  24  through the pump  22  to the nozzle  26  and from the reaction wells  12  to a collection drain  40  for collecting spent reagent. A source  29  of inert gas communicates with the nozzle for providing an inert atmosphere in the reaction well  12  and for aid in emptying the reaction well.  
         [0028]     A control system includes a drive motor controller  32  for control of the drive motor  14  and a pump controller  34  for activation of the fluid pump  22 . Both of the controllers,  32  and  34 , are in communication with a central processing unit (CPU)  36  for receiving protocol commands. A user interface  38  is provided for input of commands to the CPU  36 .  
         [0029]     Referring to  FIG. 2  and  FIG. 3 , a housing  8  is provided having a top wall  16 , a base mounting plate  58  ( FIG. 4 ) and front, rear and side walls  18  which cooperate to define an interior in which the drive motor  14 , the drive motor controller  32  and the pump controller  34  are disposed. The CPU  36  can also be located in the housing  8  or alternatively the CPU can be located on the exterior of the housing and communicate with the controllers  32  and  34  by cable or wireless communication. In the embodiment illustrated the rotatable carousel  10  comprises an annulus  42  ( FIG. 3 ) having a downwardly extending ring  44  about its inner circumference. The annulus  42  is provided with a plurality of openings  46  for communication between a reaction well  12  and the collection drain  40 . As illustrated four arcuate segments  48  are removably secured on the annulus  42  by clamping brackets  50 . As most clearly shown by  FIG. 4 , a series of reaction well cavities  52  are formed in the segment  48  for receiving corresponding reaction wells  12  and the cavities are provided with corresponding openings  54  which are aligned with the openings  46  in the annulus  42 . It will be understood that the number of arcuate segments  48  as well as the number of reaction wells  12  can be varied and modified as desired depending on such factors as, for example, the desired quantity of finished product, the number of different products to be prepared, the complexity of the reactions being carried out and other factors well understood by those skilled in the art. The carousel may contain reaction wells of different volume simultaneously.  
         [0030]     One embodiment that exemplifies a system for driving the carousel  10  is the offset driving system illustrated in  FIG. 4 . A carousel mount, shown generally as  46  consists of a fixed cylindrical outer sleeve  56 , carried on the base mounting plate  58 . Concentrically disposed in the outer sleeve  56  is a rotatable inner sleeve  59  having an open end that extends above the outer sleeve. The ring  44  of the annulus  42  is fit within the mouth of the inner sleeve for attachment of the annulus to the inner sleeve for rotation therewith. Bearing assemblies (not shown) are provided within the outer sleeve  56  for essentially friction free rotation of the inner sleeve  59  and to absorb forces imposed on the inner sleeve as the carousel  10  is being driven. A stepper motor  60  is mounted on the mounting plate  58 . A pulley  62  driven by the stepper motor  60  is drivingly connected to the inner sleeve  58  by a belt  64 . The stepper motor  60  is capable of driving the carousel  10  in either direction. The drive motor controller  32  is electronically connected to the stepper motor  60  for controlling the rotation of the carousel  10  through the stepper motor. It will be understood that other systems for driving the carousel, can be employed equally as well, for example, by connecting the carousel  10  directly to the motor  60  so long as the driving system is capable of driving the carousel in either direction. A collection drain  40  and ancillary lines are also supported on the base mounting plate  58 .  
         [0031]     Preferably, as is shown in  FIG. 5 , the reaction wells  12  are removable from the reaction well cavities  52  and can be disposable. Referring to  FIG. 6  the reaction well  12  comprises end walls  66 , sidewalls  68 , a bottom wall  70  and a closure  72  that cooperate to form a reaction chamber  74 . The closure  72  is provided with an inlet port  76  that is surrounded by an upstanding collar  78  for receiving the discharge end of the dispensing nozzle  26  during delivery of reactants to the reaction chamber  74 . Likewise, the bottom wall  70  has a drain opening  80  that communicates with a collection drain  40  for removal of reactant. Surrounding the outlet of the drain opening  80  is a housing  82  in which is located a filter element  84  and a valve  86  to prevent the back flow of drained reactant back into the reaction chamber  74 . Valve  86  also is designed to open when pressure in the reaction well  12  reaches a pre-selected level during flushing of the reaction chamber under pressurized inert gas.  
         [0032]     In a preferred embodiment the bottom wall  70  of the reaction well  12  slopes downwardly toward the drain opening  80 . The angle of slope may range from between about 1° to about 45°, preferably between about 5° and about 30° from the horizontal. This allows fluids to collect at the drain opening  80  which facilitates their removal from the reaction well. As illustrated, the longitudinal dimension of the reaction well  12  is greater than its transverse dimension. Mixing and agitation of reagents in the reaction well  12  without the necessity of a separate agitator is achieved by the orientation of the wells on the carousel  10 . As shown in  FIG. 13A  the reaction wells  12  are oriented with their longitudinal dimensions normal to the axis of rotation of the carousel  10 . Even more agitation is achieved by another embodiment, illustrated in  FIG. 13B , where the reaction wells  12  are positioned so that the longitudinal dimension is oriented at an angle to the axis of rotation of the carousel  10 . Thus the reaction well  12  may be oriented on the carousel  10  so that the longitudinal dimension ranges between 0° to about 90° to the axis of rotation of the carousel. Preferably the reaction wells  12  are oriented with their longitudinal dimension is between about  
         [0033]     As shown in  FIG. 5  the housing  82  in which the filter  84  and valve  86  is formed as part of the reaction well  12 . Alternatively, the housing  82  may be removably attached to the reaction well or attached to the annulus  42  at each of the openings  46  in the event the reaction wells are to be disposable.  
         [0034]     Another embodiment of the reaction well  12  is shown in  FIG. 12  where like reference numbers denote like parts and functions. An inverted U-shaped tube  92  communicates between the reaction chamber  74  and the drain opening  80 . The inverted U-shaped tube  92  forms a trap to prevent back flow of drained reactant into the reaction chamber  74 .  
         [0035]     When carrying out solid phase reactions the final step necessary to recover the end product is the step of cleaving the product from the solid phase. This is similar to a washing step except that the liquid from the reaction well  12  must be recovered rather than sent to waste. A recovery vessel can be aligned with the drain opening  80  from a reaction well  12  to recover the product along with the cleavage fluid. In one embodiment, carousel  10  can be adapted for conveniently capturing cleavage fluid and the final product by attachment of a recovery container to the annulus  42 . As illustrated in  FIG. 14 , where like reference numbers denote like parts and like functions, an opposed pair of L-shaped brackets  47  are disposed on the undersurface of the annulus  42  on opposite sides an opening  46  with their horizontal arms facing one another. A removable recovery container  94  is provided with a flange  96  formed about its mouth. The recovery container  94  is supported by the flange  96  and the brackets  47  with the container mouth aligned with a corresponding opening  46 . A stop (not shown) may be disposed on the annulus  42  to limit the insertion of the flange  96  of the recovery container  94  to insure its mouth is aligned with the corresponding opening  46 . Alternatively, the recovery container  94  may be attached to the housing  82  of the reaction well  12  of the type shown in  FIG. 6  by bayonet lug attachment points (not shown) on the housing and the inner surface of the recovery container adjacent its mouth.  
         [0036]     Reagents are controllably dispensed to the reaction chamber  74  at a delivery station  20 . Similarly, the reaction chamber  74  is washed with a suitable washing fluid at a wash station similar to the delivery station  20 . The number and arrangement of the delivery and wash stations varies depending on the complexity and the number of steps in the reaction protocol being carried out.  
         [0037]     In  FIG. 7  and  FIG. 8  there are illustrated six stations of which four are delivery stations  20  and two are wash stations  88 . The stations  20  and  88  are mounted on a fixed platform  90  above the carousel  10 . The fixed platform  90  is carried by supports  91  in the housing  8  in which the components of the synthesizer are contained. During a sequence of protocol steps rotation of the carousel moves the inlet port  76  of a reaction well  12  into alignment with the nozzle  26  of a desired station containing the particular reagent called for at that step of the protocol. When the protocol calls for a washing step the carousel is rotated to bring the inlet port  76  of the reaction well  12  into alignment with the nozzle  26  of the wash fluid station. Positioning of the carousel at the proper angular position is directed by the drive motor controller  32  that receives commands from the CPU  36  ( FIG. 1 ).  
         [0038]     As shown in  FIG. 9  the reagent delivery station  20  and wash station  88  comprise cartridges  100 , having a front wall  101 , side walls  104 , a rear wall  106  a bottom wall  108  and a top wall  110 , the inner surfaces of which cooperate to define a reservoir  112 . The top wall  110  is open at the mouth of the reservoir  112  and a closure  114  normally seals the reservoir mouth. A check valve  116  is disposed in an opening  118  in the closure  114  prevent vapors from leaving the reservoir  112  and to allow air into the reservoir  112  to Valve to displace the withdrawn fluid volume. The bottom wall  108  is extended past the front wall  102  and an upwardly extending member  124  having a through running bore  125  receives a syringe  126  and a syringe plunger  128 . Preferably the syringe  126  and plunger  128  are disposable.  
         [0039]     A fluid port  118  in the bottom wall  108  communicates between the reservoir  112  and a fluid supply line  120  that opens to the rear wall and extends through the bottom wall to a fluid dispensing line  130  that communicates between the syringe  126  and the dispensing nozzle  26 . A check valve  122  is disposed in the fluid supply line  122  and a plug  123  normally seals the opening of the fluid supply line at the rear wall  106  of the cartridge  100 .  
         [0040]     The top wall  110  extends beyond the front wall and a linear motor  132  is mounted thereon. A lead screw  134  operated by the linear motor for bi-directional vertical movement extends through the top wall. The extending end of the lead screw  134  carries a plunger block that, responsive to the vertical movement of the lead screw, slides vertically along the outer surface of the front wall  102 . A spaced apart upper and lower pair of fingers  138  extend from the face of the plunger block  136  and the flange of the syringe plunger  128  is received the upper and lower pair for the vertical movement of the plunger responsive to the vertical movement of the plunger block. The linear motor is in electrical communication with the pump controller  34  for control of the vertical movement of the plunger block and resultant operation of the syringe  126  through control of the linear motor.  
         [0041]     An inert gas supply line  140  extends through the bottom wall  108  for communication between a source of inert gas (not shown) and the fluid dispensing line  130  for introduction of an inert gas into a reaction well  12 . A check valve  142  in the inert gas supply line  140  prevents a back flow from the dispensing line  130  to the source of inert gas.  
         [0042]     The cartridge  100  operates in the same fashion as a washing station  88  with the following differences. For washing it is necessary to insure that the wash solution is removed from the reaction well  12 . Pressurized inert gas is introduced though the dispensing nozzle  26  to flush the reaction chamber  74 . To accomplish flushing the dispensing nozzle  26  is longer than for a regent delivery station in order to form a pressure tight seal with the inlet port  76  of the reaction well  12  during a flushing step. The longer dispensing nozzle  26  will normally interfere with the rotation of the carousel  10  and accordingly a suitable linear actuator for lifting the cartridge  100  is provided to move the dispensing nozzle out of interference to permit rotation of the carousel  10  and to lower the cartridge for a pressure tight seal between the dispensing nozzle  26  and the inlet port  76  of the reaction well  12 . The Linear Actuator may comprise any apparatus that will lift the and lower the dispensing nozzle including, but not limited to solenoids, linear motors, motors with cam/lifter, motors with lead screw drive and the like.  
         [0043]     Referring to  FIG. 10  and  FIG. 11 , where like reference numbers refer to like parts having like functions, a front and a side view of a cartridge  100  adapted for use as a washing station  88  is shown. The configuration and operation of the cartridge is as described above in connection with the cartridge of  FIG. 8 . Thus the reservoir  112  is defined by the front wall  102 , the rear wall  106  and the bottom wall  108  and is normally sealed by the closure  114 . The fluid port  118  communicates between the reservoir  112  and the fluid supply line  120 . The operation of the syringe plunger  128  is responsive to the vertical movement of the plunger block  136  as driven by the lead screw  134  and linear motor  132 . As described above the flange of the syringe plunger is disposed between the upper pair and the lower pair of fingers  138  for vertical movement with the plunger block  136 .  
         [0044]     As shown in the figures a dispensing nozzle  144  extends below the bottom wall  108  for a sealed fit in the inlet port  76  of the reaction well  12 . To provide the necessary clearance for the rotation of the carousel  10 , solenoids  146  are provided to raise the cartridge  100  so that the extended dispensing nozzle  144  is clear of the carousel  10 . The solenoids  146  may be attached to the fixed platform  90  to act against the bottom wall  70  of the cartridge  100  or may be received in sockets  148  formed in the bottom wall. In either case guide pins (not shown) on the fixed platform  90  are received in pin sockets  150  formed in the front wall  101  of the cartridge  100  to provide positioning and to guide vertical motion during the lifting sequence. The pump controller is programmed to activate and deactivate the solenoids  146 .  
         [0045]     In operation a protocol consisting of a series of sequential steps for synthesizing a compound is input to the CPU  36  from the user interface  38  or is programmed in the CPU. Instructions from the CPU  36  are sent to the drive motor controller  32  which controls the rotation of the carousel  10 . Depending on the particular protocol a reaction well  12  is rotated into alignment with a reagent delivery station  20 . The pump controller  34  causes the linear motor  132  and plunger block  136  of the cartridge  100  of the reagent delivery station to fully depress and fully retract the syringe plunger  128  which produces a vacuum in the syringe  126  to draw the desired reagent from the reservoir  112  through the fluid port  118  and fluid supply line  120  into the syringe. The pump controller  34  reverses the vertical movement of the plunger block  136  and syringe plunger  128  to dispense the reagent through the dispensing nozzle  26  into the reaction chamber  74  of the reaction well  12 . The sequence of rotation and dispensing steps are repeated until all of the reagents have been dispensed into the reaction chamber  74  of the reaction well  12 . The need for an agitator to mix the reactants in the reaction well  12  is unnecessary. The elongated shape of the reaction chamber  74  coupled with rotation of the carousel  10 , which rotates in either direction, agitates the fluids in the reaction wells to thoroughly mix the reactants. In addition to rotation during the sequence of steps called for by the protocol, the carousel can be programmed to use the drive motor  14  to agitate the reaction wells  12  with small cyclic motion at a user defined amplitude, duration and frequency.  
         [0046]     As required during the reaction, the carousel  10  is rotated to align the reaction well  12  containing the reaction product with a cartridge  100  at a wash station  88 . The cartridge  100  is normally in the raised position by the lifting action of the solenoids  146 . The pump controller  146  deactivates the solenoids lowering the cartridge  100  which is guided by the guide pins in the pin sockets to bring the extended dispensing nozzle  144  into a tight fit in the inlet port  76  of the reaction well  12 . In the case of a liquid reaction, high-pressure nitrogen, or suitable inert gas, is directed into the extended dispensing nozzle  144  to force the contents of the reaction well through the drain opening  80  for recovery of the contents. In the case of solid phase reactions, the pump controller  146  signals the linear motor  132  to cause the syringe plunger  128  to fully depress and retract to create a vacuum to draw wash fluid from the reservoir  112  of the cartridge  100 . The linear motor  132  is then commanded to depress the syringe plunger  128  to force the wash fluid into the chamber  74  of the reaction well  12 . Following this the flow of pressurized inert gas pressurizes the chamber  74  causing the valve  86  to open to flush the wash fluid from the reaction chamber through the drain opening  80  to the collection drain. The filter  84  in the filter housing  82  retains the solid phase products in the reaction chamber  74  for subsequent cleavage steps.  
         [0047]     If a cleavage step is required the recovery container  94  may be attached to the reaction well  12  as described above. In the alternative, a separate vessel may be placed beneath the carousel  10  in alignment with the drain opening  80  of the reaction well  12  undergoing cleavage. Cleavage is carried out in accordance with well-understood procedures and in the same manner as the washing steps except that the cleavage fluid and finished product are recovered for subsequent separation steps.  
         [0048]     While the cartridge  100  has been described herein as generally rectangular in shape, the particular shape of the cartridge is not critical. For example the cartridge  100  can be cylindrical with equally good results. The cartridges can be removably attached to the fixed platform  90  to provide flexibility in operation. Thus, simply replacing a cartridge containing one reagent for a cartridge containing a different reagent facilitates switching reagents according to different protocols. Removable cartridges also reduce waste of reagent and washing fluid since a cartridge can be returned to the synthesizer the next time a protocol calling for that reagent is carried out.  
         [0049]     As described above the removable segments  48  allow for flexibility in the number of reaction wells  12  on the carousel  10 . Depending on the diameter of the carousel  10  and the size of the reaction wells  12  there may conveniently be as many as 108 reaction wells and as few as one.  
         [0050]     A scanner may be employed to identify the function, location and contents of each station. For example, a scanner may read an identifying bar code, a two dimensional pixel code, a color code and the like. Fluid level monitors such as Hall effect sensors, optical sensors or other conventionally available fluid sensors may be employed to determine fluid levels in the cartridge reservoirs  24 . Means for heating or cooling the contents of the reaction well  12  can be provided, such as, for example, a thermoelectric peltier effect chiller, a resistive heating element or conductive fluid lines that circulate hot or cold fluid around the reaction wells  12  and the reservoir  112  of the cartridges  100 . In addition to the delivery stations  20  and wash stations  88 , one or more monitoring stations can be carried on the carousel for monitoring temperature, performing spectroscopic analysis of the contents of a reaction well  12 , pH, purity of the product and the like.  
         [0051]     From time to time it may be desired to carry out certain steps of a protocol on fewer than all of the reaction wells  12  on the carousel  10  or to perform certain procedures manually or on another synthesizer. In those situations the reaction wells  12  will define self contained reaction vessels that can be manipulated separately of the apparatus described herein.  
         [0052]     As will be understood by those skilled in the art, various arrangements which lie within the spirit and scope of the invention other than those described in detail in the specification will occur to those persons skilled in the art. It is therefor to be understood that the invention is to be limited only by the claims appended hereto.