Parallel semicontinuous or continuous reactors

• US 6,994,827 B2
• Filed: 06/01/2001
• Issued: 02/07/2006
• Est. Priority Date: 06/03/2000
• Status: Expired due to Term

• Current Assignee: Unchained Labs Inc.
• Original Assignee: Symyx Technologies Incorporated (Dassault Systemes SA)
• Inventors: Van Erden, Lynn, McWaid, Thomas H., Safir, Adam, Nielsen, Ralph, Tiede, Richard
• Primary Examiner(s): Warden, Jill
• Assistant Examiner(s): Gordon, Brian R.
• Application Number:
  US09/873,176
• Publication Number:
  US 20030156989A1
• Time in Patent Office: 1,712 Days
• Field of Search: 422/135, 422 99-104, 422129-131, 422/81, 738/66, 366/198, 366/172.1, 222/252
• US Class Current: 422/130
• CPC Class Codes: B01F 2101/23 Mixing of laboratory samples e.g. in preparation of analysing or testing properties of materials
• CPC Class Codes: B01F 27/1121 pin-shaped
• CPC Class Codes: B01F 27/1122 anchor-shaped
• CPC Class Codes: B01F 27/1125 with vanes or blades extending parallel or oblique to the stirrer axis
• CPC Class Codes: B01F 27/1143 screw-shaped, e.g. worms
• CPC Class Codes: B01F 27/1191 with a bent rod of non-helical configuration supported at one end
• CPC Class Codes: B01F 27/851 the receptacle being subdivided in adjacent compartments
• CPC Class Codes: B01F 35/213 of the properties of the mixtures, e.g. temperature, density or colour
• 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 2219/00283 Reactor vessels with top opening
• CPC Class Codes: B01J 2219/00308 interchangeably mounted in racks or blocks
• CPC Class Codes: B01J 2219/00335 Septa
• CPC Class Codes: B01J 2219/00337 Valves
• CPC Class Codes: B01J 2219/00342 rotary
• CPC Class Codes: B01J 2219/00353 Pumps
• 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 2219/00601 : High-pressure processes
• CPC Class Codes: B01J 2219/00689 : using computers
• CPC Class Codes: B01J 2219/00698 : Measurement and control of process parameters
• CPC Class Codes: B01J 2219/00722 : Nucleotides
• CPC Class Codes: C40B 40/14 : Libraries containing macromolecular compounds and not covered by groups C40B40/06 - C40B40/12
• CPC Class Codes: C40B 60/14 : for creating libraries
• CPC Class Codes: G01N 35/1079 : with means for piercing stoppers or septums

Abstract

Parallel semi-continuous or continuous reactors are disclosed. The parallel reactors preferably comprise four or more reaction vessels. The reaction vessels are preferably small volume reaction vessels, preferably pressure reaction vessels, and/or preferably integral with a common reactor block. The reaction vessels can comprise shaft-driven stirrers. At least two, preferably at least three or at least four liquid feed lines can provide selective fluid communication between each of the reaction vessels and one or more liquid reagent sources. Additional features, suitable in connection with parallel reactors or with single reaction vessels are also disclosed.

Claims

1. A parallel, semi-continuous or continuous, pressure reactor comprising

a reactor block comprising four or more semi-continuous or continuous reaction vessels for containing liquid reaction mixtures, each of the four or more reaction vessels being pressurizable to a pressure of not less than about 50 psig,

four or more shaft-driven impellers corresponding to the four or more reaction vessels for stirring the reaction mixtures, and

at least four liquid feed lines in selectable fluid communication with each of the four or more reaction vessels, each of the at least four liquid feed lines being in fluid communication with one or more liquid reagent source vessels, such that one or more liquid reagents can be selectively fed from the one or more source vessels to each of the four or more reaction vessels during a reaction under reaction conditions.

5. The parallel reactor of claims 1 or 2 further comprising at least one feed-pressurization station pressurizable to a pressure of not less than about 50 psig, each of the at least four liquid feed lines being in selectable fluid communication with the at least one feed-pressurization station, such that each of said at least four liquid feed lines can be selectively pressurized prior to feeding the one or more liquid reagents to the four or more reaction vessels.

6. The parallel reactor of claim 5 wherein the feed-pressurization station comprises a waste vessel.

11. The parallel reactor of claim 1 wherein the at least four liquid feed lines are provided to each of the four more reaction vessels through one or more modular feed-line subassemblies, each of the feed-line subassemblies being adapted to releasably engage the reactor block and to support at least two of said liquid feed lines passing into a respective reaction vessel.

12. The parallel reactor of claim 11 wherein the one or more modular feed-line subassemblies comprises a ferrule comprising two or more apertures adapted to sealingly support the at least two liquid feed lines when the ferrule is engaged with the reactor block.

13. The parallel reactor of claim 1 wherein the at least four liquid feed lines comprise capillaries having an inside diameter of not more than about 1 mm.

14. The parallel reactor of claim 1 wherein the at least four liquid feed lines comprise capillaries having an outside diameter of not more than about 1 mm.

15. The parallel reactor of claim 1 wherein the at least four liquid feed lines comprise fused silica capillaries.

16. The parallel reactor of claim 1 wherein the at least four liquid feed lines comprise stainless steel capillaries.

17. The parallel reactor of claim 1 wherein the at least four liquid feed lines comprise polymer capillaries.

18. The parallel reactor of claim 1 wherein each of the four or more reaction vessels is defined by or contained in a lower portion of a reaction cavity in the reactor block, the reaction cavity being further defined by an upper portion in the reactor block, the upper portion of the reaction cavity having a larger cross section, taken radially, relative to the lower portion, and the reaction cavity being sized such that two or more of the at least four liquid feed lines can be passed through the upper portion to the lower portion of the reaction cavity.

19. The parallel reactor of claim 1 wherein each of the four or more reaction vessels is defined by or contained in a reaction cavity in the reactor block, the reaction cavity having a substantially uniform cross section, taken radially.

20. The parallel reactor of claim 19 wherein the reaction cavity comprises a cylindrical reaction cavity.

21. The parallel reactor of claim 1 wherein each of the at least four liquid feed lines in fluid communication with each of the four or more reaction vessels comprises at least a first section and a second section in fluid communication with each other, the second section being releasable with respect to the first section and having a distal end positioned within the reaction vessel.

22. The parallel reactor of claim 21 wherein the first section is positioned such that it is outside of the reaction vessel, and additionally or alternatively, at least substantially uncontaminated by the liquid reaction mixture.

23. The parallel reactor of claim 21 wherein the first section is positioned such that at least a portion thereof is inside a reaction cavity that contains or defines the reaction vessel.

24. The parallel reactor of claim 1 wherein each of the least four liquid feed lines has a distal end positioned within the reaction vessel, the distal end of one or more of the liquid feed lines being positioned lower in the reaction vessel relative to the distal end of one or more other of the liquid feed lines.

25. The parallel reactor of claim 24 wherein the distal end of one or more of the liquid feed lines is positioned in the reaction vessel such that feed is delivered through such one or more liquid feed lines directly into the liquid reaction mixture, and the distal end of one or more other of the liquid feed lines is positioned in the reaction vessel such that feed is delivered through such one or more other liquid feed lines into a gaseous headspace above the liquid reaction mixture.

26. The parallel reactor of claim 1 wherein the inside diameter or cross-sectional flow area of one or more of the at least four liquid feed lines is different from the inside diameter or cross-sectional flow area for another of the at least four liquid feed lines.

27. The parallel reactor of claim 1 wherein each of the at least four liquid feed lines has a substantially circular cross-sectional area, the inside diameter of one or more of the liquid feed lines is less than about 500 μ

m, and the inside diameter for another of the liquid feed lines is about 500 μ

m or more.

28. The parallel reactor of claim 1 further comprising a parallel feed-line interface providing fluid communication between a first section and a second section of each of at least four liquid feed lines, the interface being releasable with respect to the first section and additionally or alternatively, to the second section, of each of the at least four liquid feed lines.

29. The parallel reactor of claim 1 wherein at least one liquid feed line for each of the four or more reaction vessels is in direct fluid communication with a liquid reagent source vessel.

30. The parallel reactor of claim 1 further comprising at least one feed distribution valve providing selective fluid communication between one or more liquid reagent source vessels and at least one liquid feed line for each of the four or more reaction vessels.

31. The parallel reactor of claim 1 further comprising at least one syringe-type feed pump for feeding one or more liquid reagents from one or more source vessels through one or more of the liquid feed lines to the selected one or more reaction vessels.

32. The parallel reactor of claim 1 wherein the four or more reaction vessels comprise semi-continuous flow reaction vessels.

33. The parallel reactor of claim 1 wherein the four or more reaction vessels comprise continuous-flow reaction vessels.

34. The parallel reactor of claim 1 further comprising four or more gas ports, each of the four or more gas ports providing fluid communication to a respective one of the four or more reaction vessels.

35. The parallel reactor of claim 1 further comprising four or more pairs of gas ports, each of the pairs of gas ports providing fluid communication with a respective one of the four or more reaction vessels.

36. The parallel reactor of claim 34 wherein each of the four or more gas ports comprises a gaseous feed port, a pressure monitoring port, a pressure control port, or a gaseous purge port.

37. The parallel reactor of claim 1 further comprising four or more discharge lines, each of the four or more discharge lines providing fluid communication to a respective one of the four or more reaction vessels.

38. The parallel reactor of claim 1 wherein the four or more reaction vessels comprise wells formed in the reactor block.

39. The parallel reactor of claim 1 wherein the four or more reaction vessels comprise removable liners supported by wells formed in the reactor block, each of the liners having an interior surface defining a cavity for containing a respective one of the liquid reaction mixtures, and an external surface dimensioned to fit within the wells.

40. The parallel reactor of claim 39 wherein the removable liners comprise glass vials.

41. The parallel reactor of claim 1 wherein each of the four or more reaction vessels has an aspect ratio (L/D) of at least about 1.5.

42. The parallel reactor of claim 1 wherein each of the four or more reaction vessels has an aspect ratio (L/D) of at least about 2.

43. The parallel reactor of claim 1 wherein the reactor block comprises a base block comprising four or more wells defining or containing the four or more reaction vessels, and a header block positioned over the base block to form four or more pressurizable reaction cavities, each of the four or more reaction cavities defining or containing a respective one of the four or more reaction vessels.

44. The parallel reactor of claim 43 wherein the header block supports the four or more shaft-driven impellers.

45. The parallel reactor of claim 44 further comprising a disposable header gasket situated between the base block and the header block, the disposable header gasket including four or more masking regions corresponding to the four or more reaction cavities, each of the four or more masking regions being adapted to mask a portion of the header block exposed to a respective reaction cavity.

46. The parallel reactor of claims 1, 44 or 45 further comprising four or more disposable shaft covers corresponding to the four or more shaft-driven impellers, each of the four or more shaft covers being adapted to mask at least a non-disposable portion of a shaft of a respective shaft-driven impeller received in a respective reaction cavity.

47. The parallel reactor of claim 11 wherein the reactor block comprises a base block comprising four or more wells defining or containing the four or more reaction vessels, and a header block positioned over the base block to form four or more pressurizable reaction cavities, each of the four or more reaction cavities defining or containing a respective one of the four or more reaction vessels, the header block further comprising four or more feed-line subassembly receiving ports adapted to receive respective modular feed-line subassemblies.

48. The parallel reactor of claim 1 wherein each of the four or more reaction vessels has a volume of not more than about 500 ml.

49. The parallel reactor of claim 1 wherein each of the four or more reaction vessels has a volume ranging from about 1 ml to about 100 ml.

50. The parallel reactor of claim 1 wherein each of the four or more reaction vessels is pressurizable to a pressure of not less than about 400 psig.

51. The parallel reactor of claim 1 wherein each of the four or more reaction vessels is pressurizable to a pressure ranging from about 500 psig to about 1500 psig.

52. The parallel reactor of claim 1 wherein the reactor block further comprises one or more temperature control elements for individual or modular temperature control of the four or more reaction vessels.

2. A parallel, semi-continuous or continuous, pressure reactor comprising

four or more semi-continuous or continuous reaction vessels for containing liquid reaction mixtures, each of the four or more reaction vessels having a volume of not more than about 1 liter, and being pressurizable to a pressure of not less than about 50 psig,

four or more shaft-driven impellers corresponding to the four or more reaction vessels for stirring the reaction mixtures, and

at least four liquid feed lines in selectable fluid communication with each of the four or more reaction vessels, each of the at least four liquid feed lines being in fluid communication with one or more liquid reagent source vessels, such that one or more liquid reagents can be selectively fed from the one or more source vessels to each of the four or more reaction vessels during a reaction under reaction conditions.

7. The parallel reactor of claims 2 or 3 further comprising a reactor block comprising the four or more semi-continuous or continuous reaction vessels.

3. A parallel, semi-continuous or continuous, pressure reactor comprising

four or more semi-continuous or continuous reaction vessels for containing liquid reaction mixtures, each of the four or more reaction vessels being pressurizable to a pressure of not less than about 50 psig,

at least four liquid feed lines in selectable fluid communication with each of the four or more reaction vessels, each of the at least four liquid feed lines being in fluid communication with one or more liquid reagent source vessels, such that one or more liquid reagents can be selectively fed from the one or more source vessels to each of the four or more reaction vessels during a reaction under reaction conditions,

at least one feed-pressurization station pressurizable to a pressure of not less than about 50 psig, at least a portion of each of the at least four liquid feed lines being in selectable fluid communication with the at least one feed-pressurization station, such that said portion of each of the at least four liquid feed lines can be selectively pressurized prior to feeding the one or more liquid reagents to the four or more reaction vessels.

4. The parallel reactor of claim 3 wherein the feed-pressurization station comprises a waste vessel.

8. The parallel reactor of claim 3 further comprising four or more shaft-driven impellers corresponding to the four or more reaction vessels for stirring the reaction mixtures.

9. The parallel reactor of claims 3 or 8 wherein each of the four or more reaction vessels has a volume of not more than about 1 liter.

10. The parallel reactor of claim 9 further comprising a reactor block comprising the four or more semi-continuous or continuous reaction vessels.

53. A parallel, semi-continuous or continuous, pressure reactor comprising

a reactor block comprising a base block and a header block, the base block comprising eight or more wells, each of the eight or more wells containing a removable reaction vessel for containing a liquid reaction mixture, the reaction vessels having a volume of not more than about 1 liter, the header block being removably positioned over the base block for access to the reaction vessels and for forming eight or more pressurizable reaction cavities that include the eight or more wells containing the reaction vessels, the reaction cavities being pressurizable to a pressure of not less than about 100 psig,

eight or more shaft-driven impellers corresponding to the eight or more reaction vessels for stirring the reaction mixtures, the eight or more shaft-driven impellers being supported by the header block,

at least four liquid feed lines in selectable fluid communication with each of the eight or more reaction vessels, each of the at least four liquid feed lines being in fluid communication with one or more liquid reagent source vessels, and

eight or more modular feed-line subassemblies releasably received in receiving ports in the header block, each of the eight or more feed-line subassemblies being adapted to sealingly support the at least four liquid feed lines feeding a respective reaction vessel.

54. The parallel reactor of claim 53 wherein the reactor block comprises a first modular reactor block, the parallel reactor comprising one or more additional modular reactor blocks, each of the one or more additional modular reactor blocks comprising

a base block and a header block, the base block comprising eight or more wells, each of the eight or more wells containing a removable reaction vessel for containing a liquid reaction mixture, the reaction vessels having a volume of not more than about 1 liter, the header block being removably positioned over the base block for access to the reaction vessels and for forming eight or more pressurizable reaction cavities that include the eight or more wells containing the reaction vessels, the reaction cavities being pressurizable to a pressure of not less than about 100 psig, and corresponding thereto,

eight or more shaft-driven impellers corresponding to the eight or more reaction vessels for stirring the reaction mixtures, the eight or more shaft-driven impellers being supported by the header block,

at least four liquid feed lines in selectable fluid communication with each of the eight or more reaction vessels, each of the at least four liquid feed lines being in fluid communication with one or more liquid reagent source vessels, and

eight or more modular feed-line subassemblies releasably received in receiving ports in the header block, each of the eight or more feed-line subassemblies being adapted to sealingly support the at least four liquid feed lines feeding a respective reaction vessel.

55. A parallel, semi-continuous or continuous reactor comprising four or more semi-continuous or continuous reaction vessels for containing liquid reaction mixtures, each of the four or more reaction vessels is hermetically sealable and has volume of not more than about 1 liter, at least four liquid feed lines in selectable fluid communication with each of the four or more reaction vessels, each of the at least four liquid feed lines being in fluid communication with one or more liquid reagent source vessels, four or more modular feed-line subassemblies releasably received in receiving ports in the reaction vessels or in a reactor block that defines or contains the reaction vessels, each of the four or more feed-line subassemblies supporting two or more of the at least four liquid feed lines feeding a respective reaction vessel.

59. The parallel reactor of claims 55, 56, 57 or 58 further comprising four or more shaft-driven impellers corresponding to the four or more reaction vessels for stirring the reaction mixtures.

60. The reactor of claims 55, 56, 57 or 58 wherein the four or more reaction vessels comprise semi-continuous flow reaction vessels.

61. The parallel reactor of claims 55, 56, 57 or 58 wherein the four or more reaction vessels comprise continuous flow reaction vessels.

62. The parallel reactor of claim 55, 56, 57 or 58 wherein the four or more reaction vessels comprise removable liners supported by wells formed in a reactor block, each of the liners having an interior surface defining a cavity for containing a respective liquid reaction mixture, and an external surface dimensioned to fit within a respective well.

63. The parallel reactor of claim 55, 56, 57 or 58 wherein the four or more reaction vessels are formed in a reactor block, the reactor block further comprising one or more temperature control elements for individual or modular temperature control of the four or more reaction vessels.

64. The parallel reactor of claim 55, 56, 57 or 58 wherein each of the four or more reaction vessels is pressurizable to a pressure of not less than about 50 psig.

56. A parallel, semi-continuous or continuous reactor comprising four or more semi-continuous or continuous reaction vessels for containing liquid reaction mixtures, each of the four or more reaction vessels is hermetically sealable and has a volume of not more than about 1 liter, at least four liquid feed lines in selectable fluid communication with each of the four or more reaction vessels, each of the at least four liquid feed lines being in fluid communication with one or more liquid reagent source vessels, each of the at least four liquid feed lines comprising at least a first section and a second section in fluid communication with each other, the second section being releasable with respect to the first section and having a distal end positioned within a respective one of the reaction vessels.

57. A parallel, semi-continuous or continuous reactor comprising four or more semi-continuous or continuous reaction vessels for containing liquid reaction mixtures, each of the four or more reaction vessels is hermetically sealable and has a volume of not more than about 1 liter, at least four liquid feed lines in selectable fluid communication with each of the four or more reaction vessels, each of the at least four liquid feed lines being in fluid communication with one or more liquid reagent source vessels, each of the at least four liquid feed lines having a distal end positioned within the reaction vessel, the distal end of one or more of the liquid feed lines being positioned lower in the reaction vessel relative to the distal end of one or more other of the liquid feed lines.

58. A parallel, semi-continuous or continuous reactor comprising four or more semi-continuous or continuous reaction vessels for containing liquid reaction mixtures, each of the four or more reaction vessels is hermetically sealable and has a volume of not more than about 1 liter, at least four liquid feed lines in selectable fluid communication with each of the four or more reaction vessels, each of the at least four liquid feed lines being in fluid communication with one or more liquid reagent source vessels, one or more of the at least four liquid feed lines having an inside diameter or cross-sectional flow area that differs from the inside diameter or cross-sectional flow area for another of the at least four liquid feed lines.

65. A parallel, semi-continuous or continuous, pressure reactor comprising

a reactor block comprising four or more semi-continuous or continuous reaction vessels for containing liquid reaction mixtures, each of the four or more reaction vessels being pressurizable to a pressure of not less than about 50 psig,

four or more shaft-driven impellers corresponding to the four or more reaction vessels for stirring the reaction mixtures, and

at least four liquid feed lines in selectable fluid communication with each of the four or more reaction vessels, each of the at least four liquid feed lines being in fluid communication with one or more liquid reagent source vessels, such that one or more liquid reagents can be selectively fed from the one or more source vessels to each of the four or more reaction vessels during a reaction under reaction conditions, wherein the at least four liquid feed lines are provided to each of the four more reaction vessels through one or more ferrules, the reactor block further comprising four or more receiving ports adapted to receive a respective one of the ferrules, each of the receiving ports being in fluid communication with a respective one of the reaction vessels, each of the one or more ferrules comprises

a first interior end for insertion into the corresponding receiving port in the reactor block,

a second exterior end substantially opposing the first interior end,

four or more internal apertures extending from the first interior end to the second exterior end for supporting the at least four liquid feed lines passing into a respective one of the reaction vessels, the four or more internal apertures of the ferrule being adapted to sealingly support the at least four liquid feed lines when the ferrule is engaged with the receiving port,

an external side surface including a tapered portion, the tapered portion having a smaller cross-section at positions closer to the first interior end relative to positions farther from the first interior end, the tapered portion being configured to correspond to a tapered surface defining a portion of the receiving port, and

a fastener for releasably engaging at least the tapered portion of the ferrule with the corresponding tapered surface of the receiving port.

66. A parallel, semi-continuous or continuous, pressure reactor comprising

a reactor block comprising four or more semi-continuous or continuous reaction vessels for containing liquid reaction mixtures, each of the four or more reaction vessels being pressurizable to a pressure of not less than about 50 psig,

four or more shaft-driven impellers corresponding to the four or more reaction vessels for stirring the reaction mixtures, and

at least four liquid feed lines in selectable fluid communication with each of the four or more reaction vessels, each of the at least four liquid feed lines being in fluid communication with one or more liquid reagent source vessels, such that one or more liquid reagents can be selectively fed from the one or more source vessels to each of the four or more reaction vessels during a reaction under reaction conditions,

wherein each of the four or more reaction vessels is defined by or contained in a lower portion of a reaction cavity in the reactor block, wherein the lower portion of the reaction cavity has a substantially circular cross section, taken radially, the reaction cavity being further defined by an upper portion in the reactor block, wherein the upper portion of the reaction cavity has a substantially oval cross section, taken radially, the upper portion of the reaction cavity having a larger cross section, taken radially, relative to the lower portion, and the reaction cavity being sized such that two or more of the at least four liquid feed lines can be passed through the upper portion to the lower portion of the reaction cavity.

67. A parallel, semi-continuous or continuous, pressure reactor comprising

a reactor block comprising four or more semi-continuous or continuous reaction vessels for containing liquid reaction mixtures, each of the four or more reaction vessels being pressurizable to a pressure of not less than about 50 psig,

four or more shaft-driven impellers corresponding to the four or more reaction vessels for stirring the reaction mixtures, and

at least four liquid feed lines in selectable fluid communication with each of the four or more reaction vessels, each of the at least four liquid feed lines being in fluid communication with one or more liquid reagent source vessels, such that one or more liquid reagents can be selectively fed from the one or more source vessels to each of the four or more reaction vessels during a reaction under reaction conditions, wherein each of the least four liquid feed lines in fluid communication with each of the four or more reaction vessels comprises at least a first section and a second section in fluid communication with each other, the second section being releasable with respect to the first section and having a distal end positioned within the reaction vessel, and wherein the first section comprises a polymer capillary and the second section comprises a stainless steel capillary.