Rapid characterization of polymers for combinatorial, analytical and process control applications

• US 6,475,391 B2
• Filed: 02/06/2001
• Issued: 11/05/2002
• Est. Priority Date: 04/03/1998
• Status: Expired due to Term

• Current Assignee: Intermolecular Incorporated (Merck & Co., Inc.)
• Original Assignee: Symyx Technologies Incorporated (Dassault Systemes SA)
• Inventors: Lee, Thomas S., Petro, Miroslav, Safir, Adam, Nielsen, Ralph B., Fréchet, Jean M. J.
• Primary Examiner(s): Drodge, Joseph W.
• Application Number:
  US09/778,241
• Publication Number:
  US 20010027949A1
• Time in Patent Office: 637 Days
• Field of Search: 210/97, 210/134, 210/143, 210/198.2, 210/511, 210/634, 210/635, 210/656, 210/659, 73/615.2, 73/615.5, 73/615.6, 436/161, 436/174, 436/180, 436/179, 422/63, 422/65, 422/69, 422/70, 422/100, 422/101, 356/337, 356/338, 356/339, 585/899
• US Class Current: 506/12
• CPC Class Codes: B01D 15/08 Selective adsorption, e.g. chromatography
• CPC Class Codes: B01D 15/14 relating to the introduction of the feed to the apparatus
• CPC Class Codes: B01D 15/1871 placed in series
• CPC Class Codes: B01D 15/1885 placed in parallel
• CPC Class Codes: B01D 15/34 Size selective separation, e.g. size exclusion chromatography, gel filtration, permeation
• 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 19/26 Nozzle-type reactors, i.e. the distribution of the initial reactants within the reactor is effected by their introduction or injection through nozzles
• CPC Class Codes: B01J 2219/00274 Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
• CPC Class Codes: B01J 2219/00585 Parallel processes
• CPC Class Codes: B01J 2219/00587 High throughput processes
• CPC Class Codes: B01J 2219/00707 separated from the reactor apparatus
• 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: G01N 15/0205 by optical means
• CPC Class Codes: G01N 2015/0288 Sorting the particles
• CPC Class Codes: G01N 2015/0294 Particle shape
• CPC Class Codes: G01N 2030/324 speed, flow rate
• CPC Class Codes: G01N 30/02 Column chromatography
• CPC Class Codes: G01N 30/16 Injection G01N30/24 takes precedence
• CPC Class Codes: G01N 30/24 Automatic injection systems
• CPC Class Codes: G01N 30/30 : of temperature
• CPC Class Codes: G01N 30/461 : with serial coupling of separation columns
• CPC Class Codes: G01N 30/466 : with separation columns in parallel
• CPC Class Codes: G01N 30/54 : Temperature
• CPC Class Codes: G01N 30/6052 : body
• CPC Class Codes: G01N 30/88 : Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
• CPC Class Codes: G01N 33/44 : Resins; Plastics; Rubber; Leather
• CPC Class Codes: G01N 35/085 : Flow Injection Analysis
• CPC Class Codes: G01N 35/1097 : characterised by the valves valves in general F16K
• CPC Class Codes: Y10T 436/25 : including sample preparation

Abstract

A method is disclosed for characterizing a plurality of non-biological polymer samples. The method includes the steps of injecting four or more non-biological polymer samples into a mobile-phase of a liquid chromatography system, chromatographically separating at least one sample component or polymer molecule of each of the four or more injected polymer samples from other sample components or polymer molecules thereof in a chromatographic column, and serially detecting a property of the four or more non-biological polymer samples or of components or polymer molecules thereof with a flow-through detector at an average sample throughput of not more than about 10 minutes per sample.

Claims

1. A method for characterizing a plurality of non-biological polymer samples, the method comprising

serially injecting four or more non-biological polymer samples into a mobile phase of a high-performance liquid chromatography system,

introducing each of the four or more injected samples into a chromatographic column, the chromatographic column comprising separation media having a polymeric stationary phase effective for chromatographic separation of sample components or polymer molecules thereof,

chromatographically separating at least one sample component or polymer molecule of each of the four or more injected polymer samples from other sample components or polymer molecules thereof in the chromatographic column, and

serially detecting a property of the four or more non-biological polymer samples or of components or polymer molecules thereof with a flow-through detector at an average sample throughput of not more than about 10 minutes per sample.

2. The method of claim 1 wherein the polymeric stationary phase is a cross-linked resin.

3. The method of claim 1 wherein the polymeric stationary phase is a polystyrenic stationary phase.

4. The method of claim 3 wherein the polymeric stationary phase is a poly(styrene-divinylbenzene) stationary phase.

5. The method of claim 4 wherein the average sample-throughput is not more than about 30 seconds per sample.

6. The method of claim 4 wherein the average sample-throughput is not more than about 20 seconds per sample.

7. The method of claim 4 wherein the average sample-throughput is not more than about 10 seconds per sample.

8. The method of claim 1 wherein the polymeric stationary phase is a polymethacrylate stationary phase.

9. The method of claim 8 wherein the polymeric stationary phase is a stationary phase selected from the group consisting of hydroxylated polyglycidyl methacrylates and poly(hydroxyethylmethacrylate).

10. The method of claim 1 wherein the separation media is effective for size exclusion chromatography.

11. The method of claim 1 wherein the four or more polymer samples are 8 or more polymer samples, and the average sample-throughput is not more than about 8 minutes per sample.

12. The method of claim 11 wherein the average sample-throughput is not more than about 4 minutes per sample.

13. The method of claim 11 wherein the average sample-throughput is not more than about 2 minutes per sample.

14. The method of claim 11 wherein the average sample-throughput is not more than about 1 minute per sample.

15. The method of claim 1 wherein the polymer samples are selected from the group consisting of polymer solutions, polymer emulsions and polymer dispersions.

16. The method of claim 1 wherein each of the four or more polymer samples comprise a polymer component, a monomer component and a continuous fluid phase.

17. The method of claim 1 wherein each of the four or more polymer samples comprise a copolymer component, a first comonomer component, a second comonomer component and a continuous fluid phase.

18. The method of claim 1 further comprising determining a property of interest from the detected property.

19. The method of claim 18 wherein the determined property is selected from the group consisting of weight-average molecular weight, number-average molecular weight, viscosity-average molecular weight, peak molecular weight, polydispersity index and molecular-weight-distribution shape.

20. The method of claim 18 wherein the determined property is selected from the group consisting of composition and conversion.

21. The method of claim 1 wherein the chromatographic column comprises a stationary-phase and the sample components or polymer molecules of the first and second samples are separated from other respective components or polymer molecules thereof by introducing the samples onto the stationary phase and subsequently eluting the samples or components thereof from the stationary phase with an eluant, the method further comprising

controlling the column geometry, stationary-phase, eluant composition, eluant temperature or eluant flow rate such that the sample-throughput is not more than about 10 minutes per sample.

37. The method of claims 1 or 33 wherein the detected property is selected from the group consisting of emitted light, refracted light, absorbed light and scattered light.

38. The method of claims 1 or 33 wherein the property is detected with a detector selected from the group consisting of a refractive-index detector, an ultraviolet-visual detector, a photodiode array detector, a static-light-scattering detector, a dynamic-light-scattering detector, an evaporative-light-scattering detector and a capillary viscometer detector.

39. The method of claims 1 or 33 wherein the chromatographic column comprises a porous stationary-phase effective for size exclusion chromatography and has an aspect ratio ranging from about 0.1 to about 1.

40. The method of claims 1 or 33 wherein the property is detected with a combination of detectors comprising a static light-scattering detector and a mass detector.

41. The method of claims 1 or 33 wherein the property is detected with a combination of detectors comprising a static-light-scattering detector and at least one of a refractive index detector or an evaporative light-scattering detector.

42. The method of claims 1 or 33 wherein the property is detected with a combination of detectors comprising the light-scattering detector and at least one of a UV-VIS detector or a photodiode array detector.

43. The method of claims 1 or 33 wherein the property is detected with a combination of detectors comprising the light-scattering detector and a viscometric detector.

44. The method of claims 1 or 33 wherein the sample concentration is known, and a property is detected with a refractive index detector.

22. A method for characterizing a plurality of non-biological polymer samples, the method comprising

withdrawing a first non-biological polymer sample into an injection probe of an autosampler, the sample being withdrawn from a polymerization process line, a sample line in fluid communication therewith, or from a sample container,

preparing the withdrawn first sample for chromatographic analysis,

injecting at least a portion of the prepared first sample into a mobile phase of a liquid chromatography system at a first injection time, t_LCI1,

chromatographically separating at least one sample component or polymer molecule of the injected first sample from other sample components or polymer molecules thereof in a chromatographic column,

detecting a property of at least one of the separated sample components or polymer molecules of the first sample,

withdrawing a second non-biological polymer sample into the injection probe, the sample being withdrawn from the same sample container or from a different sample container, or alternatively, from a sample line in fluid communication with a polymerization process line, or from a polymerization process line,

preparing the withdrawn second sample for chromatographic analysis,

injecting at least a portion of the prepared second sample into the mobile phase of the liquid chromatography system at a second injection time, t_LCI2, the difference in injection time, t_LCI2−

t_LCI1, being not more than about 10 minutes,

chromatographically separating at least one sample component or polymer molecule of the injected second sample from other sample components or polymer molecules thereof in the chromatographic column, and

detecting a property of at least one of the separated sample components or polymer molecules of the second sample.

23. The method of claim 22 wherein the withdrawn second sample is prepared while separating or detecting the withdrawn first sample.

24. The method of claim 22 further comprising cleaning the injection probe after injecting at least a portion of the first sample into the mobile phase of the liquid chromatography system and before withdrawing the second sample.

25. The method of claim 22 wherein the first and second polymer samples are withdrawn from a polymerization process line, or from a sample line in fluid communication therewith.

26. The method of claim 22 wherein the first and second samples are withdrawn from a container which is in fluid communication with a polymerization process line, or from a container which is in fluid communication with a sample line which is in fluid communication with a polymerization process line.

27. The method of claim 22 wherein the polymerization process line is an industrial polymerization process line.

28. The method of claim 22 wherein the difference in injection time, t_LCI2−

t_LCI1, is not more than about 4 minutes.

29. The method of claim 22 wherein the difference in injection time, t_LCI2−

t_LCI1, is not more than about 2 minutes.

30. The method of claim 22 wherein the difference in injection time, t_LCI2−

t_LCI1, is not more than about 1 minute.

31. The method of claim 22 wherein

the liquid chromatography system comprises a pump for providing flow of a mobile phase from a mobile-phase fluid source through one or more chromatography columns to a flow-through detector, an injection port, and optionally an injection valve, the injection port and optional injection valve being internal to a heated-environment enclosure and being adaptable for fluid communication with the mobile phase for injecting the polymer samples into the mobile phase, the one or more chromatography columns being internal to the heated-environment enclosure and being adapted to separate one or more components or polymer molecules of the polymer samples from other components or polymer molecules thereof, the flow-through detector being internal or external to the heated-environment enclosure and being adapted to detect a property of the polymer samples or a component or polymer molecule thereof,

the injection probe is a heated injection probe, and the autosampler and injection probe are external to the heated-environment enclosure, the method further comprising

inserting the heated injection probe from a position external to the heated-environment enclosure into the injection port within the heated-environment enclosure for injection of the samples into the mobile phase.

32. The method of claim 22 wherein the polymer sample is a polymerization product mixture and prepared only with one or more steps selected from the group consisting of non-chromatographic separation, dilution, mixing, and redissolution.

33. A method for controlling a polymerization process, the method comprising

serially sampling a polymerization process line to obtain four or more temporally separated non-biological polymer samples therefrom,

serially detecting a property of the four or more polymer samples of components or polymer molecules thereof with a high performance liquid chromatography system at an average sample-throughput of not more than about 2 minute per sample, and

controlling the polymerization process based on the detected property or based on a property of interest determined from the detected property.

34. The method of claim 33 further comprising maintaining the polymer samples at a temperature of not less than about 100°

C. at least until the polymer samples are injected into the mobile phase of the liquid chromatography system.

35. The method of claim 33 further comprising maintaining the polymer samples at a temperature of not less than about 125°

C. at least until the polymer samples are injected into the mobile phase of the liquid chromatography system.

36. The method of claim 33 further comprising maintaining the polymer samples at a temperature of not less than about 150°

C. at least until the polymer samples are injected into the mobile phase of the liquid chromatography system.

45. A method for characterizing a plurality of non-biological polymer samples, the method comprising

withdrawing a first non-biological polymer sample into an injection probe of an autosampler, the autosampler and injection probe being external to a heated-environment enclosure,

inserting the first-sample-containing injection probe from a position external to the heated-environment enclosure into an injection port internal to the heated-environment enclosure, the injection port being in selectable fluid communication with a mobile phase of a liquid chromatography system,

injecting at least a portion of the first sample into the mobile phase of the liquid chromatography system at a first injection time, t_LCI1,

chromatographically separating at least one sample component or polymer molecule of the injected first sample from other sample components or polymer molecules thereof in a chromatographic column, the column being internal to the heated-environment enclosure,

detecting a property of at least one of the separated sample components or polymer molecules of the first sample,

withdrawing a second non-biological polymer sample into the injection probe,

inserting the second-sample-containing injection probe into the injection port,

injecting at least a portion of the second sample into the mobile phase of the liquid chromatography system at a second injection time t_LCI2, the difference in injection time, t_LCI2−

t_LCI1, being not more than about 10 minutes,

chromatographically separating at least one sample component or polymer molecule of the injected second sample from other sample components or polymer molecules thereof in the chromatographic column, and

detecting a property of at least one of the separated sample components or polymer molecules of the second sample.

46. The method of claim 45 wherein the injection probe is a heated injection probe.