Parallel reactor with internal sensing

• US 6,306,658 B1
• Filed: 12/14/1998
• Issued: 10/23/2001
• 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: Dales, G. Cameron, van Beek, Johannes A. M., VanErden, Lynn, Turner, Howard W.
• Primary Examiner(s): Soderquist, Arlen
• Application Number:
  US09/211,982
• Time in Patent Office: 1,044 Days
• Field of Search: 422/62, 422/93, 422/102, 422/104, 422/196, 422/197, 436/37, 436/147, 436/159, 436/161, 436/164, 436/172, 436/173, 436/85
• 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: B01F 35/3231 Driving several stirrer shafts, e.g. about the same axis
• 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
• CPC Class Codes: Y10T 436/115831 : Condition or time responsive
• CPC Class Codes: Y10T 436/12 : Condition responsive control

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, 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.

Claims

1. An apparatus for parallel processing of reaction mixtures comprising:

vessels sealed against fluid communication with one another and adapted for containing the reaction mixtures at pressures different than ambient pressures;

a stirring system for agitating the reaction mixtures;

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

an injection system comprising a fluid delivery probe movable from one vessel to another vessel for effecting the introduction of a fluid into each of the vessels at a pressure different than ambient pressure, said injection system being operable for preventing leakage of fluid under pressure from each vessel during said introduction by said fluid delivery probe and after said probe has moved to another vessel.

2. The apparatus of claim 1, wherein the injection system comprises:

fill ports adapted to receive a fluid delivery probe;

first conduits and valves, the first conduits providing fluid communication between the fill ports and the valves; and

second conduits and injectors, the second conduits providing fluid communication between the valves and the injectors;

wherein the injectors are located in the vessels.

3. The apparatus of claim 2, further comprising a robotic handling system, wherein the robotic handling system is adapted to manipulate the fluid delivery probe.

4. The apparatus of claim 3, further comprising a computer to control both the robotic handling system and the valves.

5. The apparatus of claim 2, wherein the fill port comprises:

an elongated body having a longitudinal axis and a bore centered on the longitudinal axis, the bore extending the length of the elongated body and characterized by first, second, and third diameters, wherein the first diameter is greater than the second diameter, and the second diameter is greater than the third diameter;

an elastomeric o-ring seated within the bore of the elongated body on a first ledge defined by the second diameter and the third diameter; and

a cylindrical sleeve having a hole centered on its axis of rotation, the hole extending the length of the cylindrical sleeve;

wherein the cylindrical sleeve is seated within the bore of the elongated body on a second ledge defined by the first diameter and the second diameter and the cylindrical sleeve abuts the elastomeric o-ring.

6. The apparatus of claim 5, wherein the cylindrical sleeve is made of a chemically resistant plastic material.

7. The apparatus of claim 6, wherein the chemically resistant plastic material is a perfluoro-elastomer or polyethylethylketone or polytetrafluoroethylene.

8. The apparatus of claim 2, wherein the fill port comprises:

an elongated body having a longitudinal axis and a bore centered on the longitudinal axis, the bore extending the length of the elongated body and characterized by a first diameter and a second diameter, wherein the first diameter is greater than the second diameter; and

a cylindrical insert having a tapered hole centered on its axis of rotation, the tapered hold extending the length of the cylindrical insert;

wherein the cylindrical insert is seated within the bore of the elongated body on a ledge defined by the first diameter and the second diameter.

9. The apparatus of claim 8, wherein the cylindrical insert is made of a chemically resistant plastic material.

10. The apparatus of claim 9, wherein the chemically resistant plastic material is a perfluoro-elastomer or polyethylethylketone or polytetrafluoroethylene.

11. The apparatus of claim 2, further comprising a reactor block;

wherein the vessels comprise wells formed in the reactor block.

12. The apparatus of claim 11, further comprising an injector manifold associated with the reactor block and wherein the fill ports and valves are in fluid communication with the injector manifold.

13. The apparatus of claim 12, wherein the injector manifold is attached to the reactor block and the first conduits and the second conduits are passageways formed in the injector manifold.

14. The apparatus of claim 12, wherein the wells comprise holes extending from a top surface of the reactor block to a bottom surface of the reactor block, the apparatus further comprising:

a lower plate disposed on the bottom surface of the reactor block, the lower plate defining a base of each of the wells;

an injector adapter plate disposed on the top surface of the reactor block, the injector adapter plate having holes substantially aligned with the wells and having channels extending from a front edge of the injector adapter plate to a bottom surface of the injector adapter plate, wherein the injectors are attached to the bottom surface of the injector adapter plate and are in fluid communication with the channels, and the injector manifold is attached to the front edge of the injector adapter plate so that the second conduits are in fluid communication with the channels of the injector adapter plate; and

an upper plate disposed on the injector adapter plate, the upper plate defining an upper end of each of the wells.

15. The apparatus of claim 14, wherein the injectors extend into the reaction mixtures.

16. Apparatus as set forth in claim 1 wherein said injection system further comprises:

fill ports for receiving said probe, said probe being movable from one fill port to another to deliver fluid;

conduits connecting the fill ports and respective vessels; and

valves for opening and closing said conduits, each valve being operable to open to permit the delivery of fluid from the probe to a respective vessel at a pressure different from ambient pressure, and to close after said delivery.

17. Apparatus as set forth in claim 16 wherein each fill port is configured for the insertion of said probe therein, said apparatus further comprising a seal in each fill port for sealing engagement with the probe when the probe is inserted in the fill port.

18. Apparatus as set forth in claim 17 wherein said valves are located in said conduits downstream from respective fill ports, and wherein each valve is operable to close before the probe is completely withdrawn from a respective fill port.

19. Apparatus as set forth in claim 16 further comprising a reactor block having a series of wells therein extending down from an upper surface of the block for removably receiving said vessels therein, and a manifold mounting the fill ports generally adjacent the upper surface of the reactor block, said conduits comprising passages in the manifold in fluid communication with said fill ports for flow of fluid from the probe to said vessels.

20. Apparatus as set forth in claim 19 wherein each fill port comprises a body attached to said manifold, a bore through the body in fluid communication with a respective passage in said manifold, and a seal in said bore adapted for sealing engagement with the probe when the probe is inserted in said bore.

21. Apparatus as set forth in claim 11 wherein said temperature control system is operable to regulate the temperature of the reaction mixture in each vessel independent of the other vessels.

22. An apparatus for parallel processing of reaction mixtures comprising:

a reactor block having a series of wells therein extending down from an upper surface of the block,

an upper plate removably secured to said reactor block over said upper surface thereof, said upper plate having openings therein in registry with the wells in the reactor block,

removable liners in the wells for containing said reaction mixtures,

a temperature control system for regulating the temperature of the reaction mixtures; and

a stirring system attached to said upper plate and removable with the upper plate for agitating the reaction mixtures, the stirring system comprising;

spindles extending down into respective wells, each of the spindles having a first end and a second end;

a stirring blade attached to the first end of each of the spindles;

a drive mechanism located external to the vessels that is adapted to rotate the spindles; and

magnetic feed through devices for magnetically coupling the drive mechanism to the second end of each of the spindles.

23. The apparatus of claim 22, wherein each of the magnetic feed through devices comprises:

a rigid cylindrical pressure barrier having an interior surface that together with one of the wells defines a closed chamber;

a magnetic driver rotatably mounted concentrically with the pressure barrier and external to the closed chamber; and

a magnetic follower rotatably mounted within the closed chamber;

wherein the drive mechanism is mechanically coupled to rotate the magnetic driver and the magnetic follower follows the magnetic driver, and the second end of one of the spindles is attached to the magnetic follower so that the spindles rotate as driven by the drive mechanism.

24. The apparatus of claim 23, wherein the drive mechanism further comprises:

a motor; and

a drive train coupling the motor to the magnetic driver of the magnetic feed through devices.

25. The apparatus of claim 23, wherein the drive train comprises:

gears attached to the motor and to the magnetic driver of the magnetic feed through devices, each of the gears dimensioned and arranged so as to mesh with at least one adjacent gear so that rotational energy is transmitted along the drive train from the motor to the spindles through the magnetic feed through devices.

26. An apparatus for parallel processing of reaction mixtures comprising:

vessels for containing th e reaction mixtures;

a temperature control system for regulating the temperature of the reaction mixtures; and

a stirring system for agitating the reaction mixtures, the stirring system comprising multi-piece spindles partially contained in the vessels, and a drive mechanism coupled to the spindles, the drive mechanism adapted to rotate the spindles;

wherein each of the spindles includes;

an upper spindle portion mechanically coupled to the drive mechanism, and

a stirrer of a chemically resistant non-metal material removably attached to the upper spindle portion and contained in one of the vessels.

27. The apparatus of claim 26, wherein the removable stirrer is made of plastic.

28. The apparatus of claim 26, wherein the chemically resistant material is a perfluoro-elastomer or polyethylethylketone or polytetrafluoroethylene or glass.

29. The apparatus of claim 26, further comprising a coupler for reversibly attaching the removable stirrer to the upper spindle portion, wherein the coupler comprises:

a cylindrical body having first and second holes centered along an axis of rotation of the coupler, the first hole dimensioned to receive an end of the upper spindle portion, and the second hole of the coupler dimensioned to receive an end of the removable stirrer.

30. The apparatus of claim 29, further including a locking mechanism for preventing relative rotation of the coupler and the removable stirrer comprising:

a pin embedded in the end of the removable stirrer;

a spring mounted between the coupler and a shoulder formed on the removable stirrer periphery; and

an axial groove extending from an entrance of the second hole to a lateral slot cut through a wall of the coupler, the lateral slot extending partway around the coupler circumference to an axial slot cut through the wall of the coupler;

wherein the axial groove, the lateral slot, and the axial slot are sized to accommodate the pin when the end of the removable stirrer is inserted into the second hole and rotated, and the pin is held in the axial slot by a force exerted by the spring.

31. The apparatus of claim 26, wherein the removable stirrer is snapped into the upper spindle portion.

32. A method of making and characterizing materials comprising the steps of:

providing vessels with starting materials to form reaction mixtures;

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

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

evaluating the reaction mixtures by tracking at least one characteristic of the reaction for at least a portion of the confining step;

wherein the confining step further includes a step of injecting a fluid into at least one of the vessels.

33. The method of claim 32, wherein the fluid of the injecting step comprises a catalyst.

34. The method of claim 32, wherein the fluid of the injecting step comprises a catalyst poison.

35. The method of claim 32, wherein the fluid of the injecting step comprises a comonomer.