Parallel reactor with internal sensing and method of using same

• US 6,548,026 B1
• Filed: 10/22/1998
• Issued: 04/15/2003
• Est. Priority Date: 08/13/1998
• Status: Expired due to Term

• Current Assignee: Unchained Labs Inc.
• Original Assignee: Symyx Technologies Incorporated (Dassault Systemes SA)
• Inventors: van Beek, Johannes A. M., Mansky, Paul, Dales, G. Cameron, Hajduk, Damian A., Nielsen, Ralph B.
• Primary Examiner(s): Warden, Jill
• Assistant Examiner(s): Sines, Brian J.
• Application Number:
  US09/177,170
• Time in Patent Office: 1,636 Days
• Field of Search: 422/224, 422/226-229, 422/231, 422/198-205, 422/131-138, 526/65, 435/305.2
• US Class Current: 422/138
• 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

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. An apparatus for parallel processing of reaction mixtures comprising:

sealed vessels for containing the reaction mixtures;

a stirring system for agitating the reaction mixtures in the sealed vessels, said stirring system comprising stirring members at least partially contained in the vessels and a drive mechanism coupled to the stirring members, the drive mechanism adapted to rotate the stirring members; and

a temperature control system that is adapted to maintain a first group of the vessels at a different temperature than a second group of the vessels;

the drive mechanism comprising a motor and a drive train coupling the motor to the stirring members.

2. The apparatus of claim 1, wherein the drive train comprises:

gears attached to the motor and to portions of the stirring members located external to the vessels, each of the gears dimensioned and arranged to mesh with at least one adjacent gear so that rotational energy is transmitted along the drive train from the motor to the stirring members.

3. The apparatus of claim 1, wherein the drive train comprises:

sprockets attached to the motor and to portions of the stirring members located external to the vessels; and

a chain linking the sprockets so that rotation energy is transmitted along the drive train from the motor to the stirring members.

4. The apparatus of claim 1, wherein the drive train comprises:

pulleys attached to the motor and to portions of the stirring members located external to the vessels; and

belts linking the pulleys so that rotation energy is transmitted along the drive train from the motor to the stirring members.

23. Apparatus as set forth in claim 1 wherein the reaction mixtures in said sealed vessels are contained at pressures different than ambient pressure.

24. Apparatus as set forth in claim 23 wherein said vessels contain reaction mixtures at pressures of at least about 16 psig.

5. An apparatus for parallel processing of reaction mixture comprising:

vessels for containing the reaction mixtures;

a stirring system for agitating the reaction mixtures, said stirring system comprising stirring members at least partially contained in the vessels and a drive mechanism coupled to the stirring members, the drive mechanism adapted to rotate the stirring members; and

a temperature control system that is adapted to maintain a first group of the vessels at a different temperature than a second group of the vessels;

each of the stirring members comprising a spindle, each spindle having a first end and a second end, a stirring blade attached to the first end of the spindle, and wherein the second end of the spindle is magnetically coupled to the drive mechanism.

25. Apparatus as set forth in claim 5 wherein saud vessels are sealed.

26. Apparatus as set forth in claim 25 wherein the reaction mixtures in said sealed vessels are contained at pressures different than ambient pressure.

27. Apparatus as set forth in claim 26 wherein said vessels contain reaction mixtures at pressures of at least about 16 psig.

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

vessels for containing the reaction mixtures;

a stirring system for agitating the reaction mixtures, said stirring system comprising stirring members at least partially contained in the vessels and a drive mechanism coupled to the stirring members, the drive mechanism adapted to rotate the stirring members; and

a temperature control system that is adapted to maintain a first group of the vessels at a different temperature than a second group of the vessels;

wherein the stirring members are magnetic stirring bars, and the drive mechanism comprises an array of electromagnets that produce rotating magnetic fields in the vessels.

7. The apparatus of claim 6, wherein the array of electromagnets is arranged so that each of the vessels is located between four electromagnets, the four electromagnets defining four corners of a quadrilateral sub-array.

8. The apparatus of claim 7, wherein the array of electromagnets is arranged so that the ratio of electromagnets to vessels is about 1:

1, 2;

1, or 4;

1.

9. The apparatus of claim 8, wherein the array of electromagnets further comprises:

a first group of electromagnets; and

a second group of electromagnets;

wherein, the first group of electromagnets are electrically connected in series so that pairs of successive electromagnets define two opposite corners of each quadrilateral sub-array, and the second group of electromagnets are electrically connected in series so that pairs of successive electromagnets define two opposite corners of each quadrilateral sub-array.

10. The apparatus of claim 6, wherein the drive mechanism further comprises:

a drive circuit and a processor, wherein the drive circuit is controlled by the processor and is adapted to independently and temporally vary electrical current in the first group of electromagnets and in the second group of electromagnets.

11. The apparatus of claim 10, wherein the drive circuit further comprises a power source that is adapted to provide sinusoidal electrical currents.

12. The apparatus of claim 10, wherein the drive circuit further comprises a power source that is adapted to provide pulsed electrical currents.

13. The apparatus of claim 6, wherein the array of electromagnets is mounted on a printed circuit board.

28. Apparatus as set forth in claim 6 wherein said vessels are sealed.

29. Apparatus as set forth in claim 28 wherein the reaction mixtures in said sealed vessels are contained at pressures different than ambient pressure.

30. Apparatus as set forth in claim 29 wherein said vessels contain reaction mixtures at pressures of at least about 16 psig.

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

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

a stirring system for agitating the reaction mixtures while maintaining the vessels sealed against fluid communication with one another, said stirring system comprising stirring members at least partially contained in the vessels, each stirring member comprising a spindle and a blade on the spindle, and a drive mechanism magnetically coupled to the stirring members for rotating the blades of the stirring members; and

a temperature control system for regulating the temperature of the vessels.

15. Apparatus as set forth in claim 14, further comprising a reactor block containing said vessels, said temperature control system comprising heating elements for heating the vessels and temperature sensors for sensing the temperatures of the vessels.

16. Apparatus as set forth in claim 14 further comprising a thermally conductive reactor block containing said vessels, said temperature control system comprising a passageway in the reactor block, a pump for pumping thermal fluid through the passageway, and temperature sensors for sensing the temperatures of the vessels.

17. Apparatus as set forth in claim 14 wherein the spindle of each stirring member has first and second ends, and wherein said blade is attached to said first end of the spindle and said second end of the spindle is magnetically coupled to said drive mechanism.

18. Apparatus as set forth in claim 14 wherein said temperature control system is operable to maintain the vessels at selected temperatures independent of one another whereby different vessels may simultaneously be maintained at different temperatures.

19. Apparatus as set forth in claim 14 wherein said temperature control system is operable to maintain a first group of vessels at a different temperature than a second group of vessels.

20. Apparatus as set forth in claim 14 wherein said vessels contain reaction mixtures at pressures of at least about 16 psig.

21. Apparatus as set forth in claim 14 further comprising a reactor block containing said vessels, and wherein the vessels comprise wells formed in the reactor block.

22. Apparatus as set forth in claim 21 further comprising removable liners in the wells for containing said reaction mixtures.