Analysis and control of parallel chemical reactions

• US 6,489,168 B1
• Filed: 01/29/1999
• Issued: 12/03/2002
• 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, Dales, G. Cameron
• Primary Examiner(s): Soderquist, Arlen
• Application Number:
  US09/239,223
• Time in Patent Office: 1,404 Days
• Field of Search: 422/62, 422/93, 422/102, 422/104, 422/196, 422/197, 422/130, 422/131, 436/37, 436/147, 436/159, 436/161, 436/164, 436/172, 436/173, 436/85, 436/43, 700/266, 700/268, 700/269
• 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

Computer programs and computer-implemented methods for monitoring the progress and properties of parallel chemical reactions. The invention repeatedly receives a measured value or values associated with the contents of each of a plurality of reactor vessels and displays the measured over the course of a combinatorial chemical reaction. Reaction parameters associated with individual reactor vessels are changed in response to the value measured during the reaction. Reaction parameters include temperature, pressure, stirring speed. The reaction occurring in one or more reactor vessels is quenched in response to values measured during the reaction. The measured values are used to calculate experimental results including temperature change, pressure change, percent conversion of starting material, and viscosity. The measured values and experimental results are displayed. In another aspect, the invention features a method for controlling a combinatorial chemical reactor. The method includes receiving set points for properties associated with the reaction environment in multiple reactor vessels, measuring experimental values associated with each reactor vessel, displaying the experimental values, and changing the vessels'"'"' reaction environment in response to input set points and changing experimental values. In another aspect, the invention features a reactor control system for monitoring and controlling a parallel chemical reaction. The system includes modules for providing control signals to a parallel chemical reactor, receiving measured values from the parallel chemical reactor and calculating experimental results from the measured values, and for receiving reaction parameters from the user and displaying the set of measured values and the calculated values.

Claims

1. A method of controlling a combinatorial chemical reactor, the reactor comprising a plurality of reactor vessels, each vessel having a reaction environment, the method comprising the steps of:

receiving a set point for a property associated with each vessel'"'"'s reaction environment;

measuring the property for each vessel'"'"'s reaction environment to obtain measured values;

simultaneously displaying the measured values associated with the contents of each of the plurality of reactor vessels in a tabular array corresponding to the plurality of reactor vessels; and

changing the reaction environment in one or more of the plurality of reactor vessels as a function of the set point and the measured values;

terminating a reaction occurring in one or more of the vessels as a function of the set point and the measured values; and

displaying a histogram of the measured values simultaneously with the displaying of the tabular array.

2. A method of monitoring a combinatorial chemistry experiment during which a plurality of reactions are simultaneously occurring substantially independent of each other in a plurality of reactor vessels, respectively, each of the plurality of vessels having a sensor providing measured values relating to a parameter of each of the plurality of reactor vessels, said method comprising the steps of:

(a) receiving measured values associated with the contents of each of the plurality of reactor vessels during the course of the reactions;

(b) providing a first window displaying in tabular form the received measured values associated with the contents of each of the plurality of reactor vessels;

(c) providing a second window displaying in graphical form the received measured values associated with the contents of each of the plurality of reactor vessels; and

(d) selectively displaying the first and second windows in response to a selection by a user.

3. A method of monitoring a combinatorial chemistry experiment during which a plurality of reactions are simultaneously occurring substantially independent of each other in a plurality of reactor vessels, respectively, each of the plurality of vessels having first and second sensors associated therewith providing first and second signals indicative of first and second properties, respectively, of the reaction in each of the plurality of vessels, said method comprising the steps of:

(a) measuring values corresponding to the first and second signals provided by the first and second sensors so that the measured values correspond to the first and second properties of the reaction in each of the plurality of vessels;

(b) receiving the measured value associated with each of the first and second sensors of each of the plurality of reactor vessels;

(c) simultaneously displaying the received measured values corresponding to a selected one of the first and second properties of the reaction in each of the plurality of reactor vessels for simultaneously monitoring the selected property of the reaction in each of the plurality of reactor vessels during the course of the reactions; and

(d) repeating steps (a), (b), and (c) multiple times for monitoring variations in the selected property in each of the plurality of reactor vessels during the course of the reactions.

4. The method of claim 3, wherein the step of receiving the measured value comprises receiving a set of values for a plurality of reaction conditions associated with each of the plurality of reactor vessels.

5. The method of claim 3 wherein the step of simultaneously displaying comprises the steps of displaying the received measured values in a tabular array corresponding to the plurality of reactor vessels and displaying a graphical representation of the received measured values such that the tabular array and the graphical representation are simultaneously displayed.

6. The method of claim 3, further comprising the step of:

quenching a catalyst in one of the plurality of reactor vessels in response to the received measured value associated with the contents of the one reactor vessel.

7. The method of claim 3 further comprising the step of:

using the received measured values to calculate a change in value of a particular parameter for one of the plurality of reactor vessels.

8. The method of claim 7, wherein the calculated change comprises at least one of the following:

temperature change, pressure change, change in percent conversion of starting material and viscosity change.

9. The method of claim 7, further comprising the step of displaying the calculated change simultaneously with displaying the received measured values.

10. The method of claim 3, further comprising the steps of:

providing a first window displaying the received measured values corresponding to the first signals associated with the contents of each of the plurality of reactor vessels;

providing a second window displaying the received measured values corresponding to the second signals associated with the contents of each of the plurality of reactor vessels;

selectively displaying the first and second windows in response to a selection by a user;

controlling a parameter of each of the reactor vessels; and

changing the parameter associated with one of the plurality of reactor vessels in response to operator input during the course of the reactions so that variations in each reaction resulting from the changed parameter are monitored and displayed for each of the plurality of reactor vessels during the course of the reactions.

11. A method of monitoring a combinatorial chemistry experiment during which a plurality of reactions are simultaneously occurring substantially independent of each other in a plurality of reactor vessels, respectively, each of the plurality of vessels having a sensor associated therewith providing a sequence of signals indicative of a property of the reaction in each of the plurality of vessels, said method comprising the steps of:

(a) measuring values corresponding to the sequence of signals provided by the sensor so that the measured values correspond to the property of the reaction in each of the plurality of vessels;

(b) receiving the measured value associated with the sensor of each of the plurality of reactor vessels;

(c) simultaneously displaying the received measured values corresponding to the property of the reaction in each of the plurality of reactor vessels for simultaneously monitoring the property of the reaction in each of the plurality of reactor vessels during the course of the reactions; and

(d) repeating steps (a), (b), and (c) multiple times for monitoring variations in the property in each of the plurality of reactor vessels during the course of the reactions;

(e) controlling a parameter of each of the reactor vessels during the course of the reactions; and

(f) changing the parameter associated with one or more of the plurality of reactor vessels during the course of the reactions in response to operator input during the course of the reactions so that variations in the property resulting from the changed parameter are monitored and displayed for each of the plurality of reactor vessels during the course of the reactions.

12. The method of claim 11, wherein the changing step maintains the reactor vessel at a predetermined set point, and wherein the control parameters comprise at least one parameter selected from the following group:

temperature, pressure and motor speed.

13. The method of claim 11 wherein the step of simultaneously displaying comprises the steps of displaying the received measured values in a tabular array corresponding to the plurality of reactor vessels and displaying a graphical representation of the received measured values such that the tabular array and the graphical representation are simultaneously displayed.

14. The method of claim 11, wherein step (d) is performed at a predetermined sampling rate.

15. The method of claim 11, further comprising the step of:

quenching a catalyst in at least one of the plurality of reactor vessels in response to the received measured value associated with the contents of the one reactor vessel.

16. The method of claim 11, further comprising the step of:

using the received measured values to calculate a change in value of a particular parameter for at least one of the plurality of reactor vessels.

17. The method of claim 16, wherein the calculated change comprises at least one of the following:

temperature change, pressure change, change in percent conversion of starting material and viscosity change.

18. The method of claim 16, further comprising the step of displaying the calculated change simultaneously with displaying the received measured values.

19. The method of claim 11 further comprising the step of:

receiving a set point for the property associated with each vessel'"'"'s reaction environment; and

wherein the step of changing comprises changing the reaction environment in one or more of the plurality of reactor vessels as a function of the set point and the measured values.

20. The method of claim 19, wherein the step of changing the reaction environment in one or more of the plurality of vessels comprises the step of terminating a reaction occurring in one or more of the vessels, the set point comprises a conversion target, and wherein the measured values comprise a change in percent conversion of starting material.

21. The method of claim 20 wherein the step of simultaneously displaying comprises the steps of displaying the received measured values in a tabular array corresponding to the plurality of reactor vessels and displaying a graphical representation of the received measured values such that the tabular array and the graphical representation are simultaneously displayed.

22. The method of claim 21 wherein the graphical representation comprises a histogram.

23. The method of claim 11 wherein an additional sensor is associated with each of the plurality of vessels for providing an additional sequence of signals indicative of an additional property of the reaction in each of the plurality of vessels, said method comprising the steps of:

(g) measuring values corresponding to the additional sequence of signals provided by the additional sensor so that the measured values correspond to the additional property of the reaction in each of the plurality of vessels;

(h) receiving the measured value associated with the additional sensor of each of the plurality of reactor vessels;

(i) simultaneously displaying the received measured values corresponding to the additional property of the reaction in each of the plurality of reactor vessels for simultaneously monitoring the additional property of the reaction in each of the plurality of reactor vessels during the course of the reactions; and

(j) repeating steps (g), (h), and (i) multiple times for monitoring variations in the additional property in each of the plurality of reactor vessels during the course of the reactions wherein variations in the additional property resulting from the changed parameter are monitored and displayed for each of the plurality of reactor vessels during the course of the reactions.

26. The computer program of claim 21 wherein the instructions for simultaneously displaying the received measured values comprises displaying a graphical representation and a tabular array of the received measured values.

24. A computer program on a computer-readable medium for monitoring a combinatorial chemistry experiment during which a plurality of reactions are simultaneously occurring substantially independent of each other in a plurality of reactor vessels, respectively, each of the plurality of vessels having first and second sensors associated therewith providing first and second signals indicative of first and second properties, respectively, of the reaction in each of the plurality of vessels, said computer program comprising instructions for:

(a) measuring values corresponding to the first and second signals provided by the first and second sensors so that the measured values correspond to the first and second properties of the reaction in each of the plurality of vessels;

(b) receiving the measured value associated with each of the first and second sensors of each of the plurality of reactor vessels;

(c) simultaneously displaying the received measured values in a tabular array corresponding to a selected one of the first and second properties of the reaction in each of the plurality of reactor vessels for simultaneously monitoring the selected property of the reaction in each of the plurality of reactor vessels during the course of the reactions; and

(d) repeating steps (a), (b), and (c) multiple times for monitoring variations in the selected property in each of the plurality of reactor vessels during the course of the reactions.

25. The computer program of claim 24, further comprising instructions for:

changing a parameter associated with at least one of the plurality of reactor vessels in response to the received measured value.

27. A reactor control system for monitoring a combinatorial chemistry experiment during which a plurality of reactions are simultaneously occurring substantially independent of each other in a plurality of reactor vessels, respectively, each of the plurality of vessels having first and second sensors associated therewith providing first and second signals indicative of first and second properties, respectively, of the reaction in each of the plurality of vessels, said system comprising:

(a) a data analysis module for measuring values corresponding to the first and second signals provided by the first and second sensors so that the measured values correspond to the first and second properties of the reaction in each of the plurality of vessels and for receiving the measured value associated with each of the first and second sensors of each of the plurality of reactor vessels;

(c) a display module for simultaneously displaying the received measured values corresponding to a selected one of the first and second properties of the reaction in each of the plurality of reactor vessels for simultaneously monitoring the selected property of the reaction in each of the plurality of reactor vessels during the course of the reactions; and

(d) a system control module for controlling parameters of each of the plurality of reactor vessels.

28. The reactor control system of claim 27, wherein the display module simultaneously displays the received measured values in a tabular array corresponding to the plurality of reactor vessels.

29. The system of claim 28, wherein the display module also displays a graphical representation of the received measured values, and the tabular array and the graphical representation are simultaneously displayed.

30. The reactor control system of claim 27 wherein the system control module changes the control signals in response to the received measured values.

31. A system for monitoring a combinatorial chemistry experiment during which a plurality of reactions are simultaneously occurring substantially independent of each other in a plurality of reactor vessels, respectively, each of the plurality of vessels, said system comprising:

(a) first and second sensors associated with each of the plurality of vessels for providing first and second signals indicative of first and second properties, respectively, of the reaction in each of the plurality of vessels

(b) a data analyzer measuring values corresponding to the first and second signals provided by the first and second sensors so that the measured values correspond to the first and second properties of the reaction in each of the plurality of vessels;

(c) a display simultaneously displaying the measured values corresponding to a selected one of the first and second properties of the reaction in each of the plurality of reactor vessels for simultaneously monitoring the selected property of the reaction in each of the plurality of reactor vessels during the course of the reactions.

32. The system of claim 31 further comprising a control controlling parameters of the reactor vessels and changing the parameters in response to the measured values.

33. The system of claim 31 wherein the display displays a graphical representation and a tabular array of the received measured values, and wherein the tabular array and the graphical representation are simultaneously displayed.

34. A method of monitoring a combinatorial chemistry experiment during which a plurality of reactions are simultaneously occurring substantially independent of each other in a plurality of reactor vessels, respectively, said method comprising the steps of:

(a) measuring first measured values provided by a first set of sensors relating to a first property of the reaction in each of the plurality of reactor vessels;

(b) measuring second measured values provided by a second set of sensors relating to a second property of the reaction in each of the plurality of reactor vessels;

(c) receiving the first measured values associated with the contents of each of the plurality of reactor vessels during the course of the reactions;

(d) receiving the second measured values associated with the contents of each of the plurality of reactor vessels during the course of the reactions;

(e) providing a first window displaying the first received measured values associated with the contents of each of the plurality of reactor vessels;

(f) providing a second window displaying the second received measured values associated with the contents of each of the plurality of reactor vessels;

(g) selectively displaying the first and second windows in response to a selection by an operator for simultaneously monitoring variations in the first and second properties of the reaction in each of the plurality of reactor vessels during the course of the reactions;

(h) controlling a parameter of each of the reactor vessels; and

(i) changing the parameter associated with one of the plurality of reactor vessels in response to operator input during the course of the reactions so that variations in the first and second properties resulting from the changed parameter are monitored and displayed in each of the plurality of reactor vessels during the course of the reactions.

35. The method of claim 34 wherein the first property is temperature and the first set of sensors is a set of temperature sensors associated with the reactor vessels, and wherein the second property is pressure and the second set of sensors is a set of pressure sensors associated with the reactor vessels.

36. A method of monitoring a combinatorial chemistry experiment during which a plurality of reactions are simultaneously occurring substantially independent of each other in a plurality of reactor vessels, respectively, each of the plurality of vessels having a sensor associated therewith providing a sequence of signals indicative of a property of the reaction in each of the plurality of vessels, said method comprising the steps of:

(a) measuring values corresponding to the sequence of signals provided by the sensor so that the measured values correspond to the property of the reaction in each of the plurality of vessels;

(b) receiving the measured value associated with the sensor of each of the plurality of reactor vessels;

(c) displaying the received measured values corresponding to the property of the reaction in each of the plurality of reactor vessels for simultaneously monitoring the property of the reaction in each of the plurality of reactor vessels during the course of the reactions;

(d) receiving from an operator a designation of one of the reactor vessels; and

(e) displaying additional information relating to the reaction of the designated reactor vessel.

37. The method of claim 36 further comprising:

providing a first window displaying the received measured values associated with each of the plurality of reactor vessels; and

providing a second window displaying synthesis information relating to the reaction in the designated reactor vessel.

38. The method of claim 36 wherein an additional sensor is associated with each of the plurality of vessels for providing an additional sequence of signals indicative of an additional property of the reaction in each of the plurality of vessels, said method comprising the steps of:

(f) measuring values corresponding to the additional sequence of signals provided by the additional sensor so that the measured values correspond to the additional property of the reaction in each of the plurality of vessels;

(g) receiving the measured value associated with the additional sensor of each of the plurality of reactor vessels; and

(h) simultaneously displaying the received measured values corresponding to the additional property of the reaction in each of the plurality of reactor vessels for simultaneously monitoring the additional property of the reaction in each of the plurality of reactor vessels during the course of the reactions.