Multi-temperature modular reactor and method of using same

• US 6,528,026 B2
• Filed: 11/19/1998
• Issued: 03/04/2003
• Est. Priority Date: 08/13/1998
• Status: Expired due to Fees

• Current Assignee: Freeslate Inc. (Unchained Labs Inc.)
• Original Assignee: Symyx Technologies Incorporated (Dassault Systemes SA)
• Inventors: Mansky, Paul, Matsiev, Leonid, McFarland, Eric, Safir, Adam, Hajduk, Damian A., Nielsen, Ralph B.
• Primary Examiner(s): Johnson, Jerry D.
• Assistant Examiner(s): NECKEL, ALEXA DOROSHENK
• Application Number:
  US09/417,125
• Publication Number:
  US 20020001538A1
• Time in Patent Office: 1,566 Days
• Field of Search: 422/99, 422/102, 422/104, 422/196, 422/197, 422/300, 422/913, 422/942, 422/948, 422/50, 422/130, 422/138, 422/68.1, 436/43
• US Class Current: 422/198
• CPC Class Codes: B01F 33/45 Magnetic mixers; Mixers with magnetically driven stirrers
• CPC Class Codes: B01F 33/71 working at super-atmospheric pressure, e.g. in pressurised vessels
• CPC Class Codes: B01F 35/213 of the properties of the mixtures, e.g. temperature, density or colour
• CPC Class Codes: B01F 35/2213 Pressure
• CPC Class Codes: B01F 35/2215 Temperature
• CPC Class Codes: B01J 19/0006 Controlling or regulating processes controlling or regulating in general G05
• CPC Class Codes: B01J 19/0013 Controlling the temperature of the process
• CPC Class Codes: B01J 19/004 Multifunctional apparatus for automatic manufacturing of various chemical products sequential reactions B01J19/0046
• CPC Class Codes: B01J 19/0046 Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays synthesis methods per se C40B50/00
• CPC Class Codes: B01J 2219/00029 Batch processes
• CPC Class Codes: B01J 2219/00162 controlling the pressure
• CPC Class Codes: B01J 2219/002 inside the reactor
• CPC Class Codes: B01J 2219/00283 Reactor vessels with top opening
• CPC Class Codes: B01J 2219/00308 interchangeably mounted in racks or blocks
• CPC Class Codes: B01J 2219/0031 the racks or blocks being mounted in stacked arrangements
• CPC Class Codes: B01J 2219/00333 Closures attached to the reactor vessels
• CPC Class Codes: B01J 2219/00335 Septa
• CPC Class Codes: B01J 2219/00351 Means for dispensing and evacuation of reagents
• CPC Class Codes: B01J 2219/00367 capillary
• CPC Class Codes: B01J 2219/00373 Hollow needles
• CPC Class Codes: B01J 2219/00389 : Feeding through valves
• CPC Class Codes: B01J 2219/00418 : using pressure
• CPC Class Codes: B01J 2219/00477 : Means for pressurising the reaction vessels
• CPC Class Codes: B01J 2219/00481 : by the use of moving stirrers within the reaction vessels
• CPC Class Codes: B01J 2219/00495 : Means for heating or cooling the reaction vessels
• CPC Class Codes: B01J 2219/00585 : Parallel processes
• CPC Class Codes: B01J 2219/0059 : Sequential processes
• CPC Class Codes: B01J 2219/00596 : Solid-phase processes
• CPC Class Codes: B01J 2219/00601 : High-pressure processes
• CPC Class Codes: B01J 2219/00686 : Automatic
• CPC Class Codes: B01J 2219/00689 : using computers
• CPC Class Codes: B01J 2219/00691 : using robots
• CPC Class Codes: B01J 2219/00695 : Synthesis control routines, e.g. using computer programs
• CPC Class Codes: B01J 2219/00698 : Measurement and control of process parameters
• CPC Class Codes: B01J 2219/00702 : Processes involving means for analysing and characterising the products
• CPC Class Codes: B01J 2219/00704 : integrated with the reactor apparatus
• CPC Class Codes: B01J 2219/0072 : Organic compounds
• CPC Class Codes: B01J 2219/00722 : Nucleotides
• CPC Class Codes: B01J 2219/00745 : Inorganic compounds
• CPC Class Codes: B01L 2200/026 : Fluid interfacing between devices or objects, e.g. connectors, inlet details
• CPC Class Codes: B01L 2300/049 : Valves integrated in closure
• CPC Class Codes: B01L 2300/06 : Auxiliary integrated devices, integrated components
• CPC Class Codes: B01L 2300/0627 : Sensor or part of a sensor is integrated
• CPC Class Codes: B01L 2300/14 : Means for pressure control
• CPC Class Codes: B01L 2300/1805 : Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks
• CPC Class Codes: B01L 3/50851 : specially adapted for heating or cooling samples laboratory heating apparatus B01L7/00; incubators C12M
• CPC Class Codes: B01L 3/50853 : with covers or lids
• CPC Class Codes: B01L 7/54 : using spatial temperature gradients
• CPC Class Codes: C40B 40/14 : Libraries containing macromolecular compounds and not covered by groups C40B40/06 - C40B40/12
• CPC Class Codes: C40B 40/18 : Libraries containing only inorganic compounds or inorganic materials
• CPC Class Codes: F28D 15/00 : Heat-exchange apparatus with the intermediate heat-transfer medium in closed tubes passing into or through the conduit walls ; Heat-exchange apparatus employing intermediate heat-transfer medium or bodies F28D17/00, F28D19/00, F28D20/00 take precedence
• CPC Class Codes: F28D 2021/0077 : for tempering, e.g. with cooling or heating circuits for temperature control of elements
• CPC Class Codes: F28F 27/00 : Control arrangements or safety devices specially adapted for heat-exchange or heat-transfer apparatus control arrangements in general G05
• CPC Class Codes: G01K 13/00 : Thermometers specially adapted for specific purposes
• CPC Class Codes: G01N 21/253 : for batch operation, i.e. multisample apparatus analytical automats G01N35/00
• CPC Class Codes: Y10T 436/10 : Composition for standardization, calibration, simulation, stabilization, preparation or preservation; processes of use in preparation for chemical testing
• CPC Class Codes: Y10T 436/11 : Automated chemical analysis
• CPC Class Codes: Y10T 436/25 : including sample preparation

Abstract

An apparatus and method for carrying out and monitoring the progress and properties of multiple reactions is disclosed. The method and apparatus are especially useful for synthesizing, screening, and characterizing combinatorial libraries, but also offer significant advantages over conventional experimental reactors as well. The apparatus generally includes multiple vessels for containing reaction mixtures, and systems for controlling the stirring rate and temperature of individual reaction mixtures or groups of reaction mixtures. In addition, the apparatus may include provisions for independently controlling pressure in each vessel. In situ monitoring of individual reaction mixtures provides feedback for process controllers, and also provides data for determining reaction rates, product yields, and various properties of the reaction products, including viscosity and molecular weight.

Claims

1. A modular reactor for analyzing chemical reactions in an array of material, comprising

at least two reactor modules, each of said reactor modules having at least one reactor vessel for receiving material therein, and

a temperature control system comprising (i) a heat transfer plate as a first temperature control device for commonly biasing said at least two reactor modules to a first predetermined temperature, said heat transfer plate being in thermal contact with said at least two reactor modules, (ii) a separate second temperature control device associated with one of the at least two reactor modules for selectively varying the temperature of said at least one reactor module to a second predetermined temperature, and (iii) a separate third temperature control device associated with another of the at least two reactor modules for selectively varying the temperature of the another reactor module to a third predetermined temperature, said first predetermined temperature being different from each of said second and third predetermined temperatures.

2. The reactor in claim 1, wherein said second predetermined temperature is equal to said third predetermined temperature.

3. The reactor in claim 1 further including insulating material disposed between said at least two reactor modules.

4. The reactor in claim 1, wherein said heat transfer plate further includes a plurality of passages for receiving a temperature control medium.

5. The reactor in claim 4, wherein said temperature control medium is a thermal fluid.

6. The reactor in claim 5, wherein said thermal fluid is a member of the set consisting of water, silicone oil and halogenated solvents.

7. The reactor in claim 1, wherein each of said temperature control devices is disposed within one of said rector modules.

8. The reactor in claim 1, wherein said temperature control device is fixedly secured to said at least one reactor module.

9. The reactor in claim 1, wherein said temperature control device is fixedly secured to said heat transfer plate.

10. The reactor in claim 1, wherein said temperature control device is a thermoelectric module.

11. The reactor in claim 10, wherein said thermoelectric module includes a heater base plate, a heater top plate and a thermoelectric device, said thermoelectric device being sandwiched between said heater base plate and said heater top plate.

12. The reactor in claim 11, wherein said thermoelectric module is sandwiched between one of said reactor modules and said heat transfer plate.

13. The reactor in claim 1, wherein said first, second or third temperature control device is an electrical heating strip.

14. The reactor in claim 13, wherein said electrical heating strip is selected from the group consisting of etched stainless steel circuit paths encased in silicon rubber, etched stainless steel circuit paths encased in polyimide, or resistive wire encased in a ceramic and metal sheath.

15. The reactor in claim 13, wherein said electrical heating strip is sandwiched between a heater base plate and a heater top plate to form an electrical heating unit, wherein one of said electrical heating units is sandwiched between one of said reactor modules and said heat transfer plate.

16. The reactor in claim 1, further including temperature sensors, wherein said temperature sensors are associated with said reactor modules for monitoring the temperature of each of said reactor modules.

17. The reactor in claim 16, wherein said heat transfer plate has a temperature sensor associated therewith.

18. The reactor in claim 17, further including a processor connected to said temperature sensor for collecting and analyzing temperature data from said heat transfer plate, wherein said processor produces a signal to vary the temperature of said heat transfer plate.

19. The reactor in claim 16, wherein said temperature sensors are one of thermocouples, thermistors or resistance thermometric devices.

20. The reactor in claim 16, further including a processor connected to said temperature sensors for collecting and analyzing temperature data from said reactor module, wherein said processor produces signals to vary the temperature of said reactor modules.

21. The reactor in claim 1, further comprising a rack for storing said reactor modules and said heat transfer plate.

22. The reactor in claim 21, further including an insulating casing for storing said rack, heat transfer plate and temperature control device.

23. The reactor in claim 22, wherein said rack is selectively removable from said casing.

24. The reactor in claim 22, wherein said heat transfer plate is fixedly secured to said rack.

25. The reactor of claim 1 wherein each of the reactor modules comprises a plurality of reactor vessels.

26. The reactor of claims 1 or 25 wherein the reactor vessels are wells.

27. The reactor of claims 1 or 25 wherein the reactor vessels are removable liners.

28. The reactor of claim 1 further comprising an analytical system comprising one or more sensors for in-situ evaluation of viscosity of the materials in each of the reactor vessels.

29. The reactor of claims 1 or 25 wherein the reactor vessels are pressure vessels or are individually contained in pressure vessels, and the reactor further comprises a pressure monitoring or control system associated with each of the reactor vessels.

30. A method for analyzing and characterizing an array of materials comprising the steps of:

providing at least two reactor modules, each having a plurality of reaction vessels;

placing material in said reaction vessels;

biasing said at least two reactor modules to a first predetermined temperature using a heat transfer plate positioned in thermal contact with said at least two reactor modules;

independently controlling the temperature of the at least two reactor modules by associating a separate temperature control device with each of said at least two reactor modules, and varying the temperature of each of said reactor modules to different second and third temperatures, respectively, said second temperature of one of the at least two reactor modules being different than said third temperature of the other of said reactor modules;

monitoring and detecting changes in the materials in-situ after the temperature of each of said reactor modules is varied; and

determining characteristics of the materials based on the detected changes.

31. The method in claim 30, wherein said monitoring and detecting step is performed at predefined intervals of time, and wherein said determining step determines said characteristics of the materials as a function of time.

32. The method of claim 31, wherein said step of varying the temperature of said reactor modules is performed at a predetermined rate, wherein said determining step determines said characteristics of the materials as a function of temperature.

33. The method of claim 30, wherein said step of determining characteristics includes comparing the detected changes of the materials in said at least two reactor modules.

34. The method of claim 30, further including the step of insulating said reactor modules from one another.

35. The method of claim 30, further including the step of insulating said at least two reactor modules form environmental conditions.

36. The method of claim 30, wherein said first predetermined temperature of said heat transfer plate is below ambient temperature.

37. The method of claim 30, wherein said heat transfer plate is maintained below said ambient temperature by flowing a thermal fluid through passages disposed in said heat transfer plate.

38. The method of claim 30, wherein said step of varying the temperature of said reactor modules includes adjusting each of said reactor modules to said second predetermined temperatures, wherein said second predetermined temperatures are above said first predetermined temperature of said heat transfer plate.

39. The method of claim 30, wherein said step of varying the temperature of said reactor modules includes adjusting at least a first of said reactor modules to a second predetermined temperature that is above said first predetermined temperature of said heat transfer plate and adjusting at least a second of said reactor modules to a second predetermined temperature that is below said first predetermined temperature of said heat transfer plate.

40. The method of claim 30, wherein said step of varying the temperature of said reactor modules includes varying an amount of electrical power supplied to said temperature control units.

41. The method of claim 40, wherein said step of varying the amount of electrical power includes pumping heat from said heat transfer plate to said reactor modules to heat said reactor modules when said current is directed in a first direction.

42. The method of claim 40, wherein said step of varying the amount of electrical power includes pumping heat from said reactor modules to said heat transfer plate to cool said reactor modules when said current is directed in a second direction.

43. The method of claim 30, wherein said step of varying the temperature of said reactor module includes varying the amount of electrical power supplied to said temperature control units to adjust the amount of heat produced by said temperature control units.

44. The method of claim 30 wherein the reactor vessels are wells.

45. The method of claim 30 wherein the reactor vessels are removable liners.

46. The method of claim 30 wherein the viscosity of the materials is determined based on the detected changes.

47. The method of claim 30 further comprising pressuring each of the reactor vessels and monitoring or controlling the pressure of each of the reactor vessels.

48. A method for analyzing, synthesizing or characterizing an array of materials comprising the steps of

providing a modular reactor comprising at least two reactor modules and a heat transfer plate in thermal contact with said at least two reactor modules, each of the reactor modules having at least one reactor vessel,

placing material in said reactor vessels,

independently controlling the temperature of the at least two reactor modules to different predetermined temperatures by biasing the at least two reactor modules using said heat transfer plate to a first predetermined temperature and independently varying the temperature of said at least two reactor modules using a separate temperature control device associated with each of the reactor modules,

evaluating the materials in situ in each of the reactor vessels.

49. The method of claim 48, wherein said first predetermined temperature is below ambient.

50. The method of claim 48, wherein said first predetermined temperature of said at least two reactor modules is maintained constant over time.

51. The method of claim 48 further comprising continuously flowing a thermal fluid through passages disposed in said heat transfer plate.

52. The method of claim 48, wherein said step of varying the temperature of said at least two reactor modules includes varying the temperature of each of said at least two reactor modules to a second and third predetermined temperature, respectively, wherein said second and third predetermined temperatures are different from each other and from said first predetermined temperature.

53. The method of claim 52, wherein said second and third predetermined temperatures are varied above said first predetermined temperature.

54. The method of claim 48, wherein said step of controlling the temperature of said reactor modules includes varying the amount of electric power supplied to separate temperature control devices associated with each of the at least two reactor modules.