Abstract:
A microwave reactor for processing a flow of a mixture, said reactor comprising a reaction chamber having an unpressurized interior and a reaction block disposed within the interior of the reaction chamber, with at least one antenna disposed within the interior of the chamber; and at least one generator of electromagnetic radiation connected to the antenna so that the flow may circulate through said reaction block, and the generator generates a radiation that is uniformly and homogeneously propagated in the chamber and is evenly absorbed by the mixture. The present invention provides embodiments of microwave reactors capable of processing reaction volumes normally found in early stage drug development and pre-clinical studies, as well as embodiments sufficient for commercial production, the designs disclosed incorporate process controls as well as high microwave field uniformity. The reactor may process batches, or may be a flow through design, or a ‘stop flow’ design whereby flow is admitted, a batch is processed and the flow is re-started.

Description:
[0001]    This application is related to United States Provisional Patent Application Serial Nos. U.S. Patent Application No. 60/998,542, filed Oct. 11, 2007; U.S. Patent Application No. 60/998,543, filed Oct. 11, 2007; and U.S. Patent Application No. 60/998,500, filed Oct. 11, 2007, all of which are owned by the assignee of the present invention and are hereby incorporated by reference as though fully set forth. 
     
    
     FIELD OF THE INVENTION 
       [0002]    The present invention relates to electronic and electromechanical devices used for processing of chemical and biological samples that are to be exposed to microwave radiation. In particular, the invention is in the field of microwave power applications, applications include the electromagnetic heating of foods and other materials, etching of semiconductor devices in plasma reactors, chemical and biochemical processing including synthesis of pharmaceutical compounds, optimizing fuel production, producing ceramics, curing epoxy and composite materials, and other microwave-enhanced material processing. 
       BACKGROUND OF THE INVENTION 
       [0003]    The addition of energy is often required to initiate or accelerate chemical reactions and enhance non-chemical processes such as drying. It is known to place reagents in microwave-permeable reaction vessels and to place the vessels in a microwave chamber for irradiation with microwaves. Devices that are capable of processing reactions in batch form are sold, for one example, by CEM Corporation of Matthews, N.C. (USA) and devices that process reactions using microwaves in a continuous flow are sold by Milestone Microwave of Shelton, Conn. (USA). 
         [0004]    Microwave Assisted Organic Synthesis (MAOS) is a tool used by medicinal chemists and similar disciplines to accelerate the speed of small scale chemical synthesis by 10-1000 fold. However, the presently available technology is not capable of controlling the microwave energy input into large volumes. This inefficiency limits the application of MAOS to the early discovery stage where the volumes processed are by nature very small. The potential advantage of being able to scale-up an MAOS reactor include: (1) consistent process protocols over all stages of drug development and API production; (2) faster drug development; (3) higher yield and reproducibility due to a uniform microwave field; (4) better process controls; (5) better supply chain management with just-in-time production; (6) reduced waste in terms of both energy and the product being processed; (7) higher energy efficiency; and (8) enhanced safety 
         [0005]    It would therefore be desirable to have microwave reactors capable of processing reaction volumes normally found in early stage drug development and pre-clinical studies, as well as embodiments sufficient for commercial production. 
       SUMMARY OF THE INVENTION 
       [0006]    These and other shortcomings of the prior art are overcome by the present invention which, in preferred embodiments provides a microwave reactor for processing a flow of a mixture, said reactor comprising a reaction chamber having an unpressurized interior and a reaction block disposed within the interior of the reaction chamber, with at least one antenna disposed within the interior of the chamber; and at least one generator of electromagnetic radiation connected to the antenna so that the flow may circulate through said reaction block, and the generator generates a radiation that is uniformly and homogeneously propagated in the chamber and is evenly absorbed by the mixture. Preferably, the reaction chamber cross-section is symmetrical and more preferably the reaction chamber is cylindrical and the chamber cross-section is circular. In preferred embodiments the reactor comprises one antenna disposed on one side of the reaction block or two antennae disposed on opposite sides of a reaction block, or in alternate embodiments comprises one an array of antennae disposed on one side of the reaction block. In certain embodiments, the reactor comprises at least two arrays of antennae disposed on opposite sides of a reactor block. The reaction block is preferably comprised of a solid section of material comprising one or more reaction channels within the solid section of material, and the reaction channels comprise one or more tubular channels. The reaction block has either a planar or a non-planar surface profile, chosen from the group consisting of concave or convex, wherein the surface profile is selected to refract the microwave field to produce a uniform within the reaction channels. In preferred embodiments, a plurality of cooling channels disposed adjacent the reaction channels are provided. The reaction block can be constructed of one or more tubes connected to a manifold and the tubes are either disposed entirely within the reaction chamber, or partially outside the chamber. The reaction block can have one or more inlets for admitting flow through a wall of the chamber. In preferred embodiments, the reactor further comprises one or more computer controlled valves for regulating the operation of the reactor. 
         [0007]    Additionally, the present invention also provides embodiments of a microwave reactor for processing a batch of a mixture that ahs the features of the flow and stop-flow embodiments. 
         [0008]    The present invention thus provides embodiments of microwave reactors capable of processing reaction volumes normally found in early stage drug development and pre-clinical studies, as well as embodiments sufficient for commercial production, the designs disclosed incorporate process controls as well as high microwave field uniformity. The reactor may process batches, or may be a flow through design, or a ‘stop flow’ design whereby flow is admitted, a batch is processed and the flow is re-started. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0009]      FIG. 1  is an elevation end view of a first embodiment of a microwave reactor assembly made in accordance with certain aspects of the present invention; 
           [0010]      FIG. 2  is a side elevation view of the microwave reactor assembly shown in  FIG. 1 ; 
           [0011]      FIG. 3  is a perspective view of a vessel block; 
           [0012]      FIG. 4  is a perspective view of an alternative vessel block design; 
           [0013]      FIG. 5  is a top plan view of a reactor vessel made in accordance with the present invention; 
           [0014]      FIG. 6  is a top plan view of an alternate design of a reactor vessel made in accordance with the present invention; 
           [0015]      FIG. 7  is an elevation view of a second embodiment of a microwave reactor assembly made in accordance with the present invention; 
           [0016]      FIG. 8  is an elevation view of an alternate embodiment of a microwave reactor assembly; 
           [0017]      FIG. 9  is an elevation view of another embodiment of a microwave reactor assembly made in accordance with certain aspects of the present invention; 
           [0018]      FIG. 10  is a schematic illustration of the flow of pressurizing gas to a microwave reactor made in accordance with the present invention; 
           [0019]      FIG. 11  is an illustration of a clamping mechanism used to secure the lid of a microwave reactor made in accordance with the present invention; 
           [0020]      FIG. 12  is an illustration the clamping mechanism shown in  FIG. 11  when fully locked; and 
           [0021]      FIGS. 13A-13B  are an illustration of an alternative clamping mechanism used to secure the lid of a microwave reactor made in accordance with the present invention. 
       
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
       [0022]    Although the features and elements of the present invention are described in the preferred embodiments in particular combinations, each feature or element can be used alone (without the other features and elements of the preferred embodiments) or in various combinations with or without other features and elements of the present invention. 
         [0023]    As used herein “microwave reactor” includes, but is not limited to, a mechanical or electromechanical or all electronic device. As used herein, “microwave” includes all electromagnetic frequencies useful for material processing, primarily spectral ranges from radio frequency (RF, approximately 100 MHz minimum) to about 10 THz. As used herein “generator” might be a magnetron, a klystron, a gyrotron, or other microwave generator. 
         [0024]    The present invention discloses a plurality of planar antennae operating in one or more frequency band. The exact arrangement of antennae depends on the shape of the vessel and chamber. The design of the antennae or antennae arrays set forth below is well within the ambit of those of ordinary skill in the art to design, test and implement without undue experimentation. 
         [0025]    Referring now to  FIG. 1 , there is shown a first embodiment of the present invention, a microwave reactor  100  that is particularly well suited for scale-up flow-through and stop-flow processing. As discussed below with reference to other embodiments of the present invention, the design disclosed is optimal for certain volumes of reactor vessels but is not necessarily limited to these volumes, nor is the design limited to particular power levels, temperatures or pressures. As will be understood by those familiar with the design and construction of these devices, advancements in materials and control technologies permit an endless number of variations as the design disclosed is scaled from the smallest reaction vessel to the largest. 
         [0026]    In a preferred embodiment, seen in the cut away end view elevation in  FIG. 1  and a cross-section side elevation in  FIG. 2 , a reactor  100  is comprised of an unpressurized microwave chamber  110  encompassing a microwave transparent vessel. One or more microwave antennae  120  distribute microwave radiation created by one or more magnetrons  122  over a vessel  130 , preferably from both sides, and most preferably as uniformly as possible. Typically, a conductive backplane with coax shield  121 , which may or may not be perforated is disposed between the antenna  120  and the walls of the chamber  110 . In the embodiment illustrated, the vessel  130  is an array of flow channels  132  and cooling channels  134  designed to achieve optimal processing. The reactor  100  can be operated in either flow-through or stop-flow modes with minimal additional supporting systems. Post-processing rapid cooling can be done either within the vessel  130  or in a stage after the material being processed exits the chamber  110 . This design disclosed herein is compact and simple to make, maintain and operate. As noted above, scaling the design and increasing the reactor capacity is relatively easy to effect as well. 
         [0027]    A side view of the reactor  100  shown in  FIG. 1  is illustrated in  FIG. 2 . In the embodiment illustrated, it is seen that there are four antennae  120  as described above. Four separate magnetrons  122  are also shown, but it will be understood that in certain embodiments, less than one magnetron  122  per antenna  120  can be employed. As also seen in  FIG. 2 , the chamber  110  is sealed by two endplates  112 . The cooling channels  134  extend through the endplates  112 , through an insulator block  114  to permit cooling fluid to flow through the vessel block  130 . The mixture channels  132  similarly flow through the endplates  112  and through tubing bends  136  that permit mixture flow as described below. The tubing bends  136  are separate from but sealed with the vessel block  130  so that the latter can be replaced or switched as need be when the end plates  112  are removed. 
         [0028]    Referring now to  FIGS. 3 and 4 , there is shown a cross-section, in perspective, of a vessel block  130  that is used in the reactor design illustrated in  FIGS. 1-2 . The vessel block  130  may be rectangular in cross-section as shown or can be shaped to conform to the walls of the chamber  110 . The vessel block  130  includes mixture channels  132  and coolant channels  134 , as described above, and is preferably made of microwave transparent material that can hold high pressure and conduct heat, which is also a material that is not chemically reactive. In one embodiment, the channels  132  are a continuous Teflon tube is inserted through a block and manifold (as described below) to isolate the mixture. Then tube is replaced instead of the entire block when it becomes dirty. The channels  132  (or the opening that receive a tube) can have a circular or elliptical or other cross-section. As seen by comparing  FIG. 3  with  FIG. 4  the surface  131  can be a planar surface or can be shaped to concentrate and focus the microwave power on the mixture channels, depending on the dielectric properties of the vessel. 
         [0029]    Typically, the vessel load volume is limited by the penetration depth of the processed mixture. Circular channels extending the entire chamber length are preferably spaced about one diameter apart, plus an additional distance “X” (where distance X provides sufficient material for mechanical strength to withstand typically up to 350 psi although higher pressures will be accommodated in certain embodiments) over the entire chamber width. The number of channels is N=W/(2R+X). The total irradiated volume is then V=pR̂2 L N. If X can be small compared to R, then V is proportional to R, and therefore wavelength, as well as chamber area (W L), independent of whether the channels are oriented lengthwise or widthwise. The volume can be increased by increasing L and N (i.e. width) and the wavelength. 
         [0030]    In a flow plate such as the vessel block  130  illustrated, the fluid speed S, the flow rate F and processing time T are respectively F=□pR̂2SN and T=L/S in parallel format or F=□pR2S and T=NL/S in serial format. The product of flow rate and processing time equals the volume (V=FT), and is independent of channel configuration. Inversely, the processing rate (i.e. flow rate) is generally F=V/T in either flow-through or stop-flow mode. Therefore, to achieve sufficient processing rate, the volume must be large enough for a given processing time. The chamber area and wavelength should be chosen accordingly. The microwave antenna system would then be designed to irradiate the entire vessel uniformly with sufficient microwave intensity to drive the process at its optimal rate. 
         [0031]    For one example for a particular embodiment that is by no means limiting, given R=D=1.5 cm at 2.45 GHz microwave frequency, and choosing W=50 cm, L=100 cm, and X=1 cm, then N=12 and V=8 liters. If the processing time is T=1 min, then the fluid speed is S=12 m/min (in serial configuration) and the processing rate is F=8 L/min. A minimum 1 L/min in stop-flow mode and 10 L/min in flow-through mode is typical for commercial reactors, although the present invention is not limited to these flow rates. Employing microwave radiation at a frequency of about 915 MHz allows R=D˜4 cm, or 2.5 times the irradiated volume in a given chamber, with a resulting flow rate of F=20 L/min. 
         [0032]    As seen by comparing  FIGS. 3 and 4 , the vessel block  130  can be designed in several ways depending on material and channel configuration. The position of the vessel block  130  is chosen to optimize vertical homogeneity of absorption or intensity of the microwave intensity over the processed material volume. In certain embodiments a solid block of microwave transparent material with straight channels extending through it (as shown in  FIGS. 3 and 4 ). The block  130  may have flat external surfaces, for simplicity in manufacture and calculating the microwave field distribution, as seen in  FIG. 3  or shaped profiles to refract the fields in a desired pattern, such as to produce a more uniform microwave intensity within the channels, as seen in  FIG. 4 . The channels  132 , 134  are included for either transporting the processing mixture  132  or a fluid coolant  134 . The primary channels  132  for carrying the processing mixture may have a circular cross-section, for ease in manufacture, or other shape to achieve better performance such as uniformity of microwave absorption. Secondary channels  134  are optionally included to carry microwave transparent coolant (as shown in  FIGS. 3 and 4 ). If the secondary channels  134  are omitted, cooling would occur in a post processing stage outside of the microwave chamber  110 . The material and channel configuration would allow for the vessel block  130  to hold high pressure in the primary channels  132 . The coolant channels  134  and chamber  110  are preferably maintained at or near atmospheric pressure. 
         [0033]    Referring now to  FIG. 5 , in another embodiment, the mixture channels  132  are formed by microwave transparent tubes, which have an external “U” shaped bend  133  at each end. The tubes  132  are preferably be embedded in a microwave transparent matrix, sealed to the bends  133  that are in turn welded to the endplate  112 , thereby forming a vessel block  130  substantially as described above. Cooling occurs in a post processing stage outside of the microwave chamber, unless coolant tubes are incorporated in the matrix, or a combination of the two methods can be used. In yet another embodiment, the mixture channel tubing  132  is joined into continuous and seamless pipe snaking throughout the chamber without extending out of the chamber at each turn, as shown  FIG. 6 . To provide strength, if necessary, the tubes would be preferably embedded in a microwave transparent matrix, forming a vessel block  130  similar to that illustrated in  FIGS. 3-4 . Cooling occurs in a post processing stage outside of the microwave chamber unless coolant tubes are incorporated in the matrix, or a combination of the two methods can be used. Also visible in  FIG. 5  is the double inlet pressure valve  140  for admitting two components directly, and the back pressure valve and outlet  142  for cooled processed liquid. For stop-flow mode, the mixture directed to the inlet  140 . For flow-through mode, cooling liquid would only be directed to this end. The flow is created and controlled by a pump  144  and its associated electronics. In another embodiment, in the absence of any embedding matrix, cooling within the chamber  110  using a structure similar to that shown in  FIGS. 3 and 4  is achieved by submerging the mixture tubes  132  in a microwave transparent fluid coolant. The coolant is contained in a microwave transparent tank surrounding the tubes. The channels are connected either in series, parallel, or possibly in parallel series groups, by manifolds integrated into the endplates of the chamber. These manifolds may be simple tubes as shown in  FIGS. 3-6 , or are in certain embodiments more complex structures to achieve the desired mixture flow pattern. Temperature sensors and agitators (e.g. ultrasonic or passive vanes) could be implemented in the manifolds to monitor mixture temperature and provide stirring during processing. The manifolds would be insulated to prevent heat loss during processing. The vessel and manifolds would either be made of non-reactive material or coated with a non-reactive material such as Teflon, PEEK, sapphire, diamond or glass. 
         [0034]    The advantage of designing the vessel block  130  as described herein is simplicity in fabrication and installation in the chamber  110 . The chamber  110  is made of standard components: cylindrical chamber  110  (with mounted antennae  120 ), two endplates  112  (with plumbing fixtures) as seen in  FIG. 2 , and vessel block  130 . High pressure seals are formed by pressing the stainless steel tubing, welded into the endplates  112  and with elastomer o-rings mounted on the stems, into the channels in the vessel block  130 . These seals allow for differential thermal expansion. Maintenance is done by removing one endplate and then pulling out vessel block  130 . Operation requires electrical feed and cooling water, depending upon the capacity of the reactor and the velocity of the flow . The vessel block  130  and endplates  112  could be replaced as needed or a set could be used specifically for each process. 
         [0035]    Typically, in the vessel shown in  FIGS. 1-6  the volume in the mixture channels  132  would not be irradiated; this volume is typically relatively small in the embodiment shown in  FIG. 3 . However, the design can be optimized if desired. In flow-through mode, all parts of the mixture will be exposed to the same conditions over the entire process. So long as the flow rate is of sufficient velocity, those skilled in the art will appreciate that active stirring is unnecessary. Appropriately designed passive mixing elements in the manifolds and/or microwave permeable passive mixing elements in the channels achieves sufficient mixing. In stop-flow mode, active stirring is done by actuators in the manifolds. 
         [0036]    Stop-flow processing can be implemented by circulating mixture through the block in a closed loop. One or more valves can be used to direct flow in a circulatory manner through a pump and back to the vessel when stop-flow processing is desired. Alternatively, stop-flow processing can be done in a non-circulating geometry, requiring active mixing elements to achieve mixing, by closing upstream and downstream valves controlling flow through the vessel. The valves could be activated to choose between stop-flow and continuous flow-through processing modes. The pump operates at high pressure but only produces a low differential pressure to produce sufficient flow rates. Passive mixing elements are optionally installed in the manifolds to cause mixing as the fluid flows passed them (not illustrated). It will be appreciated by those of skill in the art that the plumbing and pump can in certain embodiments be difficult to maintain and clean and this should be taken into consideration when designing the system. 
         [0037]    The chamber  110  may be cylindrical with circular, elliptical, rectangular or some other cross-section depending on the requirements for strength against vessel failure and microwave intensity distribution. The chamber axis and the vessel are preferably but not necessarily oriented horizontally to minimize convection and thermal gradients. 
         [0038]    The pressure of the mixture undergoing processing is preferably maintained by adjustable pressure regulating valves at the input and outlet of the vessel. Typically multiple components that don&#39;t mix well are injected directly into the vessel. For this purpose, as illustrated in  FIGS. 5 and 6 , two or more input valves  150 , 152  could be installed. Pumps in each input line prior to the valves  150 , 152  maintain sufficient pressure for valve control. In stop-flow mode, in order to maintain pressure during heating, mixture can be released through the in-line outlet valve or through a second outlet valve into an unprocessed waste line. 
         [0039]    Temperature is controlled by modulating the microwave power in response to feedback provided by temperature sensors installed in the manifolds. For example, the sensors could be model number FTP-ALO or FTP-PEEK probe offered by Photon Control of Burnaby, BC Canada. Because magnetron microwave sources require several minutes to stabilize, electronically controlled ferrite attenuators are preferably installed to provide approximately real-time repeatable power adjustment. This is important because microwave-assisted reaction times have been measured or speculated to be faster than one minute. 
         [0040]    The rapid cooling required in the various embodiments is also a design consideration. In stop-flow mode, if coolant circulates through the vessel block, then rapid cooling can be done following processing while the mixture circulates through the vessel block. Once the processed mixture is cool enough (i.e. below the boiling point of all important components), it is pushed out of the vessel by pumping in the next vessel charge. However, in flow-through mode or if no coolant circulates within the vessel block, the processed mixture can be released by a pressure regulating valve into a chamber preferably although not necessarily with internal or surrounding cooling coils that may also achieve cooling by a Joule-Thomson process, i.e., expansion through a valve. This chamber is in certain embodiments filled with mixture from the previous processing run. Any initial evaporation is condensed again as the cooling chamber pressure quickly builds and as the mixture cools. 
         [0041]    In certain embodiments, spectroscopic monitoring of the reaction progress is preferably but not necessarily implemented through optical fibers mounted in the manifolds. For example, Photon-Control and Ocean Optics of Dunedin, Fla. (oceanoptics.com) offers very compact fiber coupled UV-Vis, Vis-NIR and Raman spectrometer systems for chemical analysis. RF spectroscopy is implemented by modulating the microwave carrier, or even introducing a separate signal, in order to induce a response in the mixture that is picked up by an antenna. 
         [0042]    Additionally, in certain embodiments, electromagnet coils are incorporated into the chamber in order to induce nuclear magnetic resonance (NMR) signals for chemical identification. Alternatively, a small volume could be extracted continuously during processing and fed through an NMR unit for real time analysis of the process progress. 
         [0043]    Suitable microwave transparent materials may be PEEK (PolyEtherEtherKetone), Teflon, PTFE, Polyethylene, Polypropylene, Pyrex, quartz, sapphire etc. PEEK is machinable, chemically inert and resistant, used in autoclaves, rated to 260 C, and survives 3000+ sterilization cycles. 
         [0044]    In preferred embodiments, a reactor system made in accordance with the present invention is equipped with one or more of the following diagnostic and control features. Diagnostic indicators would include real-time sensing of the chamber pressure, mixture temperature (at one or more points), rate of stirring, delivered microwave power, and spectroscopy (for example, UV-Vis absorption and/or Raman). All sensor information is then preferably but not necessarily recorded at user defined intervals and displayed graphically and as text, in combination or separately. Microwave distribution is certified so that absorbed microwave power density can be inferred. Data are preferably streamed to computer memory so that a record of all process conditions is available for future reference. In terms of control, the user control interface could consist of a ‘Prepare’, ‘Start’, and ‘Emergency Stop’ buttons and a keypad for entering all necessary parameters. The ‘Emergency Stop’ function is triggered if the handle is moved during processing (breaking an interlock), or pressure changes drastically, or the over-pressure valve opens, or coolant pressure drops, or any sensor malfunctions. The user could select the level and rate of change (1st derivative) of chamber pressure, mixture temperature (at one or more points), rate of stirring, and delivered microwave power over an essentially unlimited sequence of time intervals of arbitrary length. All of the diagnostic information would be used to control and stabilize the process conditions through proportional-integral-differential (PID) algorithms. Pressure must be released in a safe manner. 
         [0045]    It has been found that a comparison of diagnostic curves reveals that internal energy released due to the chemical reaction itself could be distinguished from heating directly due to microwave energy absorption. Such a comparison would help in understanding the dynamics of processing and selection of optimal parameters. 
         [0046]    Referring now to  FIGS. 7-8  an alternate embodiment of a reactor design made in accordance with the present invention is illustrated. This embodiment is a “batch” design and is particularly well suited for discovery and pre-clinical applications in the pharmaceutical industry, particularly for batches ranging in volume from 50 mL to 10.0 L. However, as mentioned above, any of the particular embodiments disclosed herein are not necessarily limited to a particular power range, vessel size, temperature or pressure limit and in particular are not necessarily industry specific. 
         [0047]    The reactor  200  shown in  FIG. 7  is comprised of a pressurized cylindrical chamber  210  with axis oriented vertically. A cut away side elevation view is illustrated. The reactor  200  is loaded by operating and lifting the locking handle  204  and opening the lid  202 , which pivots about a hinge point  203  and when the reactor is open inserting a microwave transparent vessel  230  loaded with the mixture to be processed. A microwave antenna  220  mounted in the lid distributes the microwave radiation form a magnetron  222  uniformly over the chamber volume. In the embodiment shown there are two magnetrons  222  each coupled to its respective antenna  220 . However, other embodiments may have only one magnetron (or more than two) and may have three or more antennae. As used herein “antenna”, “antennae” and “array” are not meant to be limiting and an “array” may have one or more antennae elements or a single antenna may be considered an array. In this embodiment, an optical fiber feed through  207  for spectroscopy and temperature measurement is provided, data from which may be used to operate and regulate the system Thus, pressure and temperature are controlled independently. Cooling during and after processing is done in situ. This design is compact and is simple to make, maintain and operate. Increasing the reactor capacity is relatively easy to effect based on the original design. 
         [0048]    As seen above with reference to  FIGS. 1 and 2 , the chamber is a preferably right cylinder with flat or curved profile floor and ceiling. The cross-section may be circular and ceiling and floor profile elliptical for better strength to weight ratio or another shape. The chamber dimensions and microwave antenna design are chosen to optimize microwave intensity over the chamber volume where the processed material resides. Vertical vanes (ribs) could be welded to the floor and ceiling to provide sufficient mechanical strength and rigidity under maximum operating pressure in the chamber. Cooling coils  250  are welded to or machined into the floor, as seen in  FIG. 7 . Coolant is circulated in the coils  250  after processing to rapidly cool the processed mixture to below its boiling point at one atmosphere before extraction; coolant could be heated or drained (forced by pressurized gas) from the coils  250  during processing to influence the mixture temperature. As the chamber  210  should not become hot the touch, the chamber floor and coils  250  are designed for (a) minimal thermal conductivity with the mixture inside during processing in the absence of coolant in the coils and (b) maximal thermal conductivity with coolant filling the coils. The bottom exterior of the chamber may also include vanes to be air cooled during processing when the coils are drained. 
         [0049]    In the embodiment shown in  FIG. 7 , to reduce evaporation, to protect chamber from corrosion and to ease cleaning, a removable liner  212  of thin, robust (thermally and chemically), microwave transparent plastic is inserted in the lower half of the chamber  210  and a removable, microwave transparent, rigid disk (barrier)  214  is snapped onto the lid  202 , thereby covering the antennae  220 . The barrier disk  214  presses on the rim of the liner  212  when the chamber lid  102  is closed, forming a hermetically sealed container within the chamber  210  that does not significantly degrade the homogeneity of the microwave field. The rigid barrier disk  214  presses on liner rim when closed, and creates a low point in center to direct splashes and condensation back into vessel, while a rim lip to stop drips. Orifices  209  covered by plastic, spring-loaded caps or spheres on either side of the lid ensure the vessel interior is maintained within a nominal pressure difference (a few psi) relative to the chamber  210 . Several orifices  209  or a large orifice, higher pressure threshold relief valve are added in certain embodiments to prevent possible over-pressure of the vessel  200  due to valve failure. Note that presence of the liner  212  and barrier disk  214  should not significantly affect the microwave intensity distribution or the pressure distribution within the chamber  210 . 
         [0050]    The vessel  230  is any of a number of designs, such as a standard beaker (Pyrex or quartz or plastic) or other microwave transparent, flat bottomed container with diameter up to the diameter of the floor (or size that is the size of the floor regardless of shape) and with height sufficient to prevent spilling and with a large mouth. In order to avoid extreme microwave intensity gradients vertically within the mixture, the depth of the mixture should not be greater than the penetration depth of the mixture, typically 1.5 cm at 2.45 GHz and 4 cm at 915 MHz. A cylindrical chamber diameter of 40 cm would then provide a maximum mixture volume of 2 litres and 5 litres respectively. In order to maintain intensity [or absorption] homogeneity vertically through the vessel  230 , the vessel  230  should be positioned at an optimal height corresponding roughly to an anti-node of the microwave field. Correct positioning of the vessel height is achieved by placing the vessel either on the liner  212  in the bottom of the chamber  210  on a microwave transparent, thermally conductive slab underneath the liner  210 , filling the region between the chamber floor and vessel bottom, or on a thin, electrically isolated, metal disk placed on top of the liner  212 , which must be thick enough to prevent breakdown between the disk and the chamber floor. The chamber floor, slab, liner and vessel most preferably have high thermal conductivity for rapid cooling. In certain embodiments, a small amount of microwave transparent fluid placed in the bottom of the chamber and the liner would improve thermal conductivity. Alternatively, the chamber  210  could be coated with a non-reactive, microwave transparent film, such as Teflon® to allow the chamber bottom to be used as the vessel. A further alternative is that the vessel  210  could be a flexible microwave transparent, sealed container (i.e., a bag) with a plugged spout. Preferably, the plug has pressure relief valves similar to that described above for the barrier disk  214 , and in such an embodiment, the barrier disk  214  would not be necessary. During processing, the container would be over-pressured relative to the chamber  210  and therefore fully inflate. Orifices  211  covered by plastic, spring-loaded caps or balls on either side of the lid ensure the vessel interior is maintained within a nominal pressure difference (a few psi may be sufficient) relative to the chamber. The container would be lifted out of the chamber after processing and drained through the spout. Temperature and spectroscopy are sensed through the container wall via the port  207  described above or the spout is attached to a plug incorporating the temperature and spectrometer probes, so that the probes are inside the container during processing. The container  210  is preferably placed on a microwave transparent or metallic plate in the chamber  210  that has a contoured profile and moves, possibly chaotically, in order to effectively mix the container contents. In certain embodiments, the plate rises during processing and lowers to make thermal contact with the cooling mechanism in the floor. In a further alternative several beakers are processed simultaneously and a microwave absorbing fluid bath added in the bottom of the liner for more uniform heating. 
         [0051]    As noted above, the embodiment of a reactor  200  made in accordance with the present invention illustrated in  FIGS. 7 and 8  is intended for batch mode operation. The chamber  210  is opened by turning the handle  204  and lifting the lid  202 , which in turn operates a rack and pinion and clamp ring  205  that act as a sealing mechanism, described in further detail below. The liner  212  and barrier disk  214  are cleaned or replaced as necessary. An uncovered, charged vessel  230  is placed on the chamber floor. An appropriate, clean stirring structure  206  is snapped onto the stirring axle  208 , its associated motor, and the sensors are positioned for the vessel  210  to be processed. Preferably, the stirring rod  208  acts as a mechanical coupling rod, and is comprised of a metallic material for a coaxial cavity. In one preferred embodiment, a TFE stirring paddle  206  that is asymmetric for better stirring is used. The paddle  206  snaps on to glass stirring axle  208  and is replaced for each batch processed with correct size for the vessel being used. In other embodiments, magnetic stirring alternative may be employed, as known in the art. Magnetic stirring motor(s) are attached to the bottom of the reactor and magnet stir bars are placed in vessel. For large area vessels, an array of stir bars would be employed. 
         [0052]    To process a batch, the lid  202  is closed and the handle  204  is turned until a safety interlock is set. The chamber pressure is increased to the desired processing value while the magnetron source  222  is allowed to reach stable operation. Microwave power is modulated to maintain the mixture at the desired temperature time profile. After processing, the mixture temperature is reduced sufficiently by circulating coolant in the cooling coils  250 . Chamber pressure is reduced to atmosphere. The handle  204  is turned, lid lifted, and the vessel  210  is removed. In the embodiment shown, cooling channels  252  are milled into chamber floor and also serve as strengthening ribs, a plate  254  secured to bottom to contain coolant. The coolant inlet  256  and the coolant outlet  258  permit coolant to flow through the structure. The coolant inlet  256  is preferably positioned in the center of the reactor bottom plate and channels designed to direct coolant flow symmetrically outward to ensure more uniform conditions. Alternatively, the inlet  256  and outlet  258  are positioned on the on the side of the reactor so as not to interfere with magnetic stirring motors described above. The cooling components are preferably made from a material such as aluminum. Operation requires electrical (possibly near 10 3 kW), high pressure gas (possibly inert or combined with reagents), and cooling water (possibly 50 psi, 4 L/min, unless a closed circuit chiller is used) utilities. 
         [0053]    Finally, referring to  FIGS. 9 and 10 , yet another alternate embodiment of the present invention is illustrated. This embodiment is a “stop-flow” design and is particularly well suited for pre-clinical and clinical applications in the pharmaceutical industry, and in particular for processing between about 2 L and 10 L of mixture. However, as mentioned above, any of the particular embodiments disclosed herein are not necessarily limited to a particular power range, vessel size, temperature or pressure limit and in particular are not necessarily industry specific. Referring now to  FIG. 9 , a side view elevation of an embodiment of a stop-flow reactor  300  made in accordance with the present invention is illustrated. The illustrated embodiment shares many of the components and features of the other embodiments of the present invention illustrated and described above with reference to  FIGS. 1-8  and these descriptions will not be repeated. The reactor  300  is comprised of a pressurized cylindrical chamber  310  with axis oriented vertically. The reactor  300  is loaded by a valve controlled inlet port  305  directing the mixture to be processed into a microwave transparent vessel  330  mounted inside the chamber  310 . One or more microwave antenna  320  mounted in the lid  302  and the floor distribute microwave radiation created by the magnetrons  322  uniformly over the vessel volume. Pressure and temperature are controlled independently, using controls known in the art. Post-processing rapid cooling is done by coiling coils or on extraction from the vessel through an outlet port. The design illustrated in  FIG. 9  is compact and is fairly simple to make, maintain and operate. Increasing the capacity of the reactor is relatively easy based on the design disclosed. The chamber  310  is preferably a right cylinder with flat floor and ceiling. The cross-section is preferably circular for better strength to weight ratio, although other shapes may be used. As explained above, the chamber dimensions and microwave antenna design are chosen to optimize microwave intensity and homogeneity over the middle height cross section of the chamber where the materials to be processed are disposed. Vertical vanes (ribs) are preferably welded to the floor and ceiling to provide mechanical strength and rigidity under the stresses encountered from the operating pressure in the chamber. 
         [0054]    The vessel  330  may be made of glass (Pyrex or quartz) or other microwave transparent plastic with diameter up to the diameter of the floor. The vessel  330  is placed on a microwave transparent base to hold the mixture at an optimum height for microwave intensity [or absorption] homogeneity in the chamber  310 . In order to avoid extreme microwave intensity gradients vertically within the mixture, the depth of the mixture should not be greater than twice (given irradiation from both sides) the penetration depth of the mixture, typically around 3 cm at 2.45 GHz and 9 cm at 915 MHz. A chamber diameter of 40 cm would then allow a maximum mixture capacity of 3 litres and 9 litres respectively. Scaling up further, a diameter of 75 cm has 12 or 36 litre capacity. 
         [0055]    To reduce evaporation, a removable, microwave transparent, rigid disk (barrier)  312  is snapped onto the chamber  310 , as described above. The vessel height is such that the barrier disk  312  presses on the rim of the vessel  310  when the chamber lid  302  is closed, forming a hermetically sealed container within the chamber  310  that does not significantly degrade the homogeneity of the microwave field. Orifices  311  covered by plastic, spring-loaded caps or balls on either side of the lid ensure the vessel interior is maintained within a nominal pressure difference (a few psi may be sufficient) relative to the chamber. Note that presence of the barrier disk  312  should not significantly affect the microwave intensity distribution or the pressure distribution within the chamber. Pressure is regulated via a pressurizing gas inlet/outlet  311 . 
         [0056]    Post-processing rapid cooling of the mixture is preferably achieved by extraction of the mixture under pressure from the vessel into a cooling stage  350  possibly by the Joule-Thomson process. Alternatively, the vessel base is designed to include microwave transparent cooling coils  352  circulating microwave transparent coolant for temperature stabilization during processing and rapid cooling afterwards, as described above. 
         [0057]    The embodiment of the present invention illustrated in  FIG. 9  is denominated as a “stop-flow” device. In operation, turning the handle  304  and lifting the lid  302  open the chamber  310 . The vessel is cleaned or replaced as necessary. As described above, a stirring structure  306  is snapped onto the stirring axle  308  and the sensors are positioned correctly. The lid  302  is closed and the handle  304  is turned until the safety interlock is set. The chamber pressure is increased to the desired processing value while the magnetron  322  is allowed to reach stable operation. Mixture is admitted into the chamber  310  through an inlet port  305  by a needle valve. Microwave power is modulated to maintain the mixture at the desired temperature or power time profile. After processing, either the mixture temperature is reduced sufficiently (below the mixture boiling point) by circulating coolant via the coolant inlet  351  in the coils or the mixture is forced out of the vessel through an outlet port controlled by a second needle valve and into a cooling vessel. For the outlet position shown in  FIG. 9 , a cam  355  automatically tilts the chamber  310  so that all the mixture drains out. More mixture is admitted and the process is repeated as desired. Alternately, the chamber pressure could be cycled in each process and the mixture admitted and discharged at near atmospheric pressure. Operation requires electrical (for example, 10 5 kW), high pressure gas (either inert or combined with reagents), and cooling water (e.g., 50 psi, 4 L/min, or a closed circuit chiller is used) utilities. 
         [0058]    In either of the embodiments illustrated in  FIGS. 7-8  or  FIG. 9 , pressure in the chamber ( 210 , 310 ) is controlled through a manifold similar to that shown schematically in  FIG. 10 . High pressure gas (gaseous reactants may be included) is admitted into the chamber ( 210 , 310 ) through one adjustable valve  510  while any excess pressure is released through a second constant pressure valve  512 . If valve control is not fast enough to maintain sufficiently constant pressure, the chamber volume might be expanded to moderate fluctuations. To prevent catastrophic failure and release of the chamber contents outside, a reservoir  520  of sufficient volume is installed with a valve set  522 , 524  to release pressure into the reservoir ( 210 , 310 ) at some maximum safe value. 
         [0059]    The chamber ( 210 , 310 ) in either of the embodiments illustrated in  FIGS. 7-8  or  FIG. 9  is preferably made in two halves: the upper lid is hinged to the lower, stationary bottom and can be lifted by a handle. A counterweight or spring is preferably provided to ease lifting and maintain an open position. When closed, an elastomer o-ring provides a pressure seal. The seal faces (“o-ring grooves”) on the lid and bottom flanges could be recessed to prevent damage. Clamping is preferably achieved by the apparatus shown in  FIGS. 11 and 12 . In one motion the lid is lowered and the handle ( 204 , 304 ) is turned, preferably about 180 degrees. A pinion gear  412  attached to the handle drives a rack  414  attached to a collar  410  encircling the chamber ( 210 , 310 ) and sitting on the lid flange. Notches  411  in the collar  410  admit pins  415  welded to the lower flange when the handle is in the open position. As the handle is turned, the collar  410  rotates about the chamber axis, causing the pins to slide into the notches. The notches  411  force the flanges together when the handle is in the closed position, forming a seal. A plastic gasket bearing between the collar and lid flange allows smooth motion of the collar. In an alternative scheme, clamping could also be done by a hinged ring clamp similar to that used in “Kwik-Flange” vacuum seals shown in  FIGS. 13A and 13B , which illustrate respectively an unclamped and clamped ring. 
         [0060]    In either of the embodiments illustrated in  FIGS. 7-8  or  FIG. 9 , multiple ports in the chamber would flexibly allow various combinations diagnostic sensors. 
         [0061]    In either of the embodiments illustrated in  FIGS. 7-8  or  FIG. 9 , stirring is preferably accomplished by either mechanical or transducer coupling. In the case of a mechanical coupling could be accomplished as shown in  FIG. 1  by extending a rigid, metal or microwave transparent rod from the motor fixed to the lid exterior, through the lid and barrier disk, which also serves as a bearing, and down to near the bottom of the vessel. A removable, microwave transparent stirring structure snaps onto the end of the rod and rotates when driven by the motor. This structure may be asymmetric to improve mixture homogeneity. The rotation rate and action (constant rotation, back-and-forth or possibly chaotic action) is adjustable and controlled by the user. In embodiments using transducers, the stirring apparatus is mounted in the base and driven at sonic or ultrasonic frequencies to agitate the mixture in the vessel. Fluid added between the base and vessel would enhance the coupling efficiency. The drive frequency is adjustable and controlled by the user. The individual transducers may be driven with controlled relative phases and frequencies that may not be constant to achieve more uniform global flow and mixing. 
         [0062]    In either of the embodiments illustrated in  FIGS. 7-8  or  FIG. 9 , Temperature is preferably controlled by modulating the microwave power in reaction to signals from one or more temperature sensors (fiber-optic) fed through the chamber lid and mounted in the barrier disk. For example, the sensors could be either (a) a remote sensing Exactus Optical Thermometer by BASF, or (b) model number FTP-ALO or FTP-PEEK probe offered by Photon Control of Burnaby, BC Canada. Because magnetron microwave sources require several minutes to stabilize, electronically controlled ferrite attenuators could be installed to provide essentially real-time repeatable power adjustment. As will be understood by those skilled in the art, many microwave-assisted reaction times are under one minute and accurate and dependable timing is therefore important. 
         [0063]    In either of the embodiments illustrated in  FIGS. 7-8  or  FIG. 9 , spectroscopic monitoring of the reaction progress is preferably implemented through optical fibers. For example, Photon-Control and Ocean Optics of Dunedin, Fla. (oceanoptics.com) offers very compact fiber coupled UV-Vis, Vis-NIR and Raman spectrometer systems for chemical analysis. Common practice in the industry is to use a Raman spectrometer from Enwave Optronics, Inc. (enwaveopt.com). RF spectroscopy may be utilized by modulating the microwave carrier or even introducing a separate signal in order to induce a response in the mixture that could be picked up by an antenna. Electromagnet coils could be incorporated in the chamber in order to induce nuclear magnetic resonance (NMR) signals for chemical identification. Alternatively, a small volume could be extracted continuously during processing and fed through an NMR unit for real time analysis of the process progress. 
         [0064]    In either of the embodiments illustrated in  FIGS. 7-8  or  FIG. 9 , Suitable microwave transparent materials may be PEEK (PolyEtherEtherKetone), Teflon, PTFE, Polyethylene, Polypropylene, Pyrex, quartz, sapphire, etc. PEEK is machinable, chemically inert and resistant, used in autoclaves, rated to 260 C, and survives 3000+ sterilization cycles. 
         [0065]    In either of the embodiments illustrated in  FIGS. 7-8  or  FIG. 9 , a reactor system could be equipped with the following diagnostic and control features. 
         [0066]    Diagnostic: 
         [0067]    Real-time sensing of the chamber pressure, mixture temperature (at one or more points preferably not to exceed ten), rate of stirring, delivered microwave power, and spectroscopy (UV-Vis absorption spectroscopy and Raman are recommended). All sensor information would be recorded at user defined intervals and displayed graphically and as text, in combination or separately. Microwave distribution would be certified so that absorbed microwave power density could be inferred. Data could be streamed to computer memory so that a record of all process conditions is available for future reference. Other possible diagnostic options might include a camera for imaging the vessel during processing. 
         [0068]    Control: 
         [0069]    The user control interface could consist of a ‘Prepare’, ‘Start’, and ‘Emergency Stop’ buttons and a keypad for entering all necessary parameters. The ‘Emergency Stop’ function is triggered if the handle is moved during processing (breaking an interlock), or pressure changes drastically, or the over-pressure valve opens, or coolant pressure drops, or any sensor malfunctions. The user could select the level and rate of change (1st derivative) of chamber pressure, mixture temperature (at one or more points), rate of stirring, and delivered microwave power over an essentially unlimited sequence of time intervals of arbitrary length. All of the diagnostic information would be used to control and stabilize the process conditions through PID algorithms. Pressure should not release rapidly. 
         [0070]    From the comparison of diagnostic curves, internal energy released due to the chemical reaction itself could be distinguished from heating directly due to microwave energy absorption. Such a comparison would help in understanding the dynamics of processing and selection of optimal parameters. 
         [0071]    Those skilled in the art will recognize that the various valves and ports, plus the probes for spectroscopy and other forms of monitoring permit controlling all the parameters of the reaction precisely. In particular, the various embodiments disclosed above allow for dynamic monitoring and real time adjustment to the flow of cooling fluids in conjunction and counterbalance with the amount of microwave energy emitted into the chamber. These capabilities and the capabilities to adjust pressure and the flow of the reaction mixture (in flow through designs) provides significant advantages. The embodiments of the present invention may be implemented with any combination of hardware and software. If implemented as a computer-implemented apparatus, the present invention is implemented using means for performing all of the steps and functions described above. 
         [0072]    The embodiments of the present invention can be included in an article of manufacture (e.g., one or more computer program products) having, for instance, computer useable media. The media has embodied therein, for instance, computer readable program code means for providing and facilitating the mechanisms of the present invention. The article of manufacture can be included as part of a computer system or sold separately. 
         [0073]    It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the present invention.