Parallel reactor with internal sensing and method of using same

• US 6,455,316 B1
• Filed: 04/13/2000
• Issued: 09/24/2002
• Est. Priority Date: 08/13/1998
• Status: Expired due to Term

• Current Assignee: Freeslate Inc. (Unchained Labs Inc.)
• Original Assignee: Symyx Technologies Incorporated (Dassault Systemes SA)
• Inventors: Wang, Pei, Mansky, Paul, Turner, Howard, Dales, G. Cameron, Matsiev, Leonid, McFarland, Eric, VanErden, Lynn, Hajduk, Damian A., Nielsen, Ralph B., VanBeek, Johannes A. M.
• Primary Examiner(s): Soderquist, Arlen
• Application Number:
  US09/548,848
• Time in Patent Office: 894 Days
• Field of Search: 422/62, 422/102, 422/104, 422/93, 422/196-197, 436/34, 436/37, 436/43, 436/85, 436/147, 436/159, 436/161, 436/164, 436/173
• US Class Current: 436/37
• 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: 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: G01N 35/1079 : with means for piercing stoppers or septums
• CPC Class Codes: Y10T 436/11 : Automated chemical analysis

Abstract

Devices and methods for controlling and monitoring the progress and properties of multiple reactions are 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, and a system for injecting liquids into the vessels at a pressure different than ambient pressure. 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. Computer-based methods are disclosed for process monitoring and control, and for data display and analysis.

Claims

1. A method of making and characterizing materials, comprising:

forming chemical reaction mixtures in a plurality of reactor vessels of a parallel reactor apparatus, said apparatus comprising sensors for providing measured values relating to chemical reactions in said reactor vessels, and a processor for receiving data relating to said measured values;

confining the reaction mixture in each reactor vessel against fluid communication with the other vessels and at a pressure other than ambient pressure;

injecting a fluid into at least one of the reactor vessels while the reaction mixture in said at least one vessel is confined and at a pressure other than ambient pressure;

agitating the reaction mixtures for at least a portion of the confining step; and

using the processor to receive said date relating to said measured values of the chemical reactions in said reactor vessels.

2. A method as set forth in claim 1 wherein the reaction mixtures of said reactor vessels are agitated at the same time.

3. A method as set forth in claim 1 wherein said processor simultaneously receives data relating to said measured values of chemical reactions occurring in said reactor vessels.

4. A method as set forth in claim 1 wherein each reactor vessel has an overall capacity in a range of from about 1 ml to about 500 ml.

5. A method as set forth in claim 1 wherein said reaction mixtures are confined at pressures in a range of from about 10 psig to about 300 psig.

6. A method as set forth in claim 1 wherein said reaction mixtures are confined at pressures in a range of from about 10 psig to about 500 psig.

7. A method as set forth in claim 1 wherein fluid is injected into said at least one reactor vessel while the reaction mixture confined therein is at a pressure greater than about 10 psig.

8. A method as set forth in claim 1 wherein fluid is injected into fill ports of the reactor vessels.

9. A method as set forth in claim 1 further comprising using said processor to compare the measured values.

10. A method as set forth in claim 9 wherein said processor compares said measured values to predetermined parameters.

11. A method as set forth in claim 9 wherein said processor compares measured values relating to one reactor vessel to measured values relating to another reactor vessel.

12. A method as set forth in claim 9 further comprising using the processor to change an environmental condition in at least one of the reactor vessels in response to comparing the measured values.

13. A method as set forth in claim 9 further comprising using the processor to change the agitation in at least one reactor vessel in response to comparing the measured values.

14. A method as set forth in claim 1 further comprising using the processor to display the measured values.

15. A method as set forth in claim 1 further comprising using the processor to control the chemical reactions in said vessels in response to said measured values.

16. A method as set forth in claim 1 further comprising inputting data relating to said chemical reactions into the processor using a user interface.

17. A method as set forth in claim 16 further comprising controlling an environmental condition in at least one reactor vessel by using said user interface.

18. A method as set forth in claim 17 wherein said environmental condition is the temperature of the reaction mixture confined in at least one reactor vessel.

19. A method as set forth in claim 17 wherein said environmental condition is the pressure at which the reaction mixture is confined in at least one reactor vessel.

20. A method as set forth in claim 16 further comprising controlling the agitation of said reaction mixtures in at least one reactor vessel by using said user interface.

21. A method as set forth in claim 16 further comprising controlling the injection of fluid into at least one reactor vessel by using said user interface.

22. A method as set forth in claim 1 further comprising placing at least two liners in two separate wells in a single reactor block.

23. A method as set forth in claim 1 wherein said fluid is injected using a robotic probe movable between reactor vessels.

24. A method as set forth in claim 1 wherein said reaction mixtures are agitated by rotating a stirring member in each of said reactor vessels.

25. A method of making and characterizing materials, comprising:

forming chemical reaction mixtures in a plurality of reactor vessels of a parallel reactor apparatus, said apparatus comprising sensors for providing measured values relating to chemical reactions in said reactor vessels, and a processor for receiving and displaying data relating to said measured values;

confining the reaction mixture in each reactor vessel against fluid communication with the other vessels and at a pressure other than ambient pressure;

injecting a fluid into at least one of the reactor vessels while the reaction mixture in said at least one vessel is confined and at a pressure other than ambient pressure;

agitating the reaction mixtures for at least a portion of the confining step;

using the processor to receive and display said data relating to said measured values; and

comparing at least one characteristic of the chemical reactions in the reactor vessels based on said data.

26. A method as set forth in claim 25 wherein fluid is injected into fill ports of the reactor vessels.

27. A method as set forth in claim 25 wherein each reactor vessel has an overall capacity in a range of from about 1 ml to about 500 ml.

28. A method as set forth in claim 25 wherein said reaction mixtures are confined at pressures in a range of from about 10 psig to about 300 psig.

29. A method as set forth in claim 25 wherein said reaction mixtures are confined at pressures in a range of from about 10 psig to about 500 psig.

30. A method as set forth in claim 25 wherein fluid is injected into said at least one reactor vessel while the reaction mixture confined therein is at a pressure greater than about 10 psig.

31. Apparatus for the parallel processing of reaction mixtures, comprising:

a plurality of sealed reactor vessels for holding reaction mixtures;

a temperature control system for regulating the temperature of the reaction mixtures in the reactor vessels;

an injection system for introducing chemical reaction materials into one or more of said sealed reactor vessels while the reactor vessel is at a pressure other than ambient pressure;

a mechanism for agitating the reaction mixture in each of the sealed reactor vessels;

sensors for providing measured values relating to chemical reactions in said reactor vessels; and

a processor for receiving and comparing data relating to said measured values.

32. Apparatus as set forth in claim 31 wherein each reactor vessel has an overall capacity in a range of about 1 ml to about 500 ml.

33. Apparatus as set forth in claim 31 wherein said reaction mixtures are confined in said sealed vessels at pressures in a range of from about 10 psig to about 300 psig.

34. Apparatus as set forth in claim 31 wherein said reaction mixtures are confined in said sealed vessels at pressures in a range of from about 10 psig to about 500 psig.

35. Apparatus as set forth in claim 31 wherein said injection system comprises a fluid delvery probe, said injection system being operable for preventing leakage of fluid under pressure from a vessel after said introduction by said fluid delivery probe.

36. Apparatus as set forth in claim 35 wherein said injection system comprises a fill port or each reactor vessel.

37. Apparatus as set forth in claim 31 wherein said mechanism for agitating comprises a stirring member inside each reactor vessel.

38. Apparatus as set forth in claim 37 wherein said mechanism for agitating comprises a single motor for moving the stirring members in said reactor vessels.

39. Apparatus as set forth in claim 31 wherein said reactor vessels are removable liners in a group of wells for holding said reaction mixtures, the liners and reaction mixtures therein being removable from the wells.

40. Apparatus as set forth in claim 31 wherein said processor includes a display for displaying said data.

41. Apparatus as set forth in claim 31 further comprising a common housing for said vessels.

42. Apparatus as set forth in claim 31 further comprising a common base for said vessels.

43. Apparatus as set forth in claim 31 wherein said vessels are grouped in an array sized for bench scale use.

44. Apparatus for the parallel processing of reaction mixtures, comprising:

a plurality of sealed reactor vessels for holding reaction mixtures;

temperature control means for regulating the temperature of the reaction mixtures in the reactor vessels;

injection means for introducing chemical reaction materials into one or more of said sealed reactor vessels;

means for agitating the reaction mixture in each of said sealed reactor vessels;

means for sensing measured values relating to chemical reactions in said reactor vessels; and

means for receiving and comparing data relating to said measured values.

47. Apparatus as set forth in claims 44 or 45 wherein each reactor vessel has an overall capacity in a range of about 1 ml to about 500 ml.

48. Apparatus as set forth in claims 44 or 45 wherein said reaction mixtures are confined in said sealed vessels at pressures in a range of from about 10 psig to about 300 psig.

49. Apparatus as set forth in claims 44 or 45 wherein said reaction mixtures are confined in said sealed vessels at pressures in a range of from about 10 psig to about 500 psig.

50. Apparatus as set forth in claims 44 or 45 wherein said injection means comprises a fluid delivery probe, said injection means being operable for preventing leakage of fluid under pressure from a vessel after said introduction by said fluid delivery probe.

51. Apparatus as set forth in claim 50 wherein said injection means comprises a fill port for each reactor vessel.

52. Apparatus as set fourth in claims 44 or 45 wherein said means for agitating comprises a stirring member inside each reactor vessel.

53. Apparatus as set forth in claim 52 wherein said means for agitating comprises a single motor for moving the stirring members in said reactor vessels.

54. Apparatus as set forth in claims 44 or 45 wherein said reactor vessels comprise removable liners in a group of wells for holding said reaction mixtures, the liners and reaction mixtures therein being removable from the wells.

55. Apparatus as set forth in claims 44 or 45 further comprising a common housing for said vessels.

56. Apparatus as set forth in claims 44 or 45 further comprising a common base for said vessels.

57. Apparatus as set forth in claims 44 or 45 wherein said vessels are grouped in an array sized for bench scale use.

45. Apparatus for the parallel processing of reaction mixtures, comprising;

a plurality of sealed reactor vessels for holding reaction mixtures;

temperature control means for regulating the temperature of the reaction mixtures in the reactor vessels;

injection means for introducing chemical reaction materials into one or more of said sealed reactor vessels;

means for agitating the reaction mixture in each of said sealed reactor vessels;

means for sensing measured values relating to chemical reactions in said reactor vessels; and

means for receiving and displaying data relating to said measured values.

46. Apparatus as set forth in claim 45 wherein said means for receiving and displaying is further operable to compare at least one characteristic of the chemical reactions in the reactor.