Flow-injection analysis and variable-flow light-scattering methods and apparatus for characterizing polymers

• US 6,175,409 B1
• Filed: 04/02/1999
• Issued: 01/16/2001
• Est. Priority Date: 04/02/1999
• Status: Expired due to Term

• Current Assignee: Intermolecular Incorporated (Merck & Co., Inc.)
• Original Assignee: Symyx Technologies Incorporated (Dassault Systemes SA)
• Inventors: Kuebler, Sigird C., Bennett, James, Petro, Miroslav, Safir, Adam, Nielsen, Ralph B.
• Primary Examiner(s): Font, Frank G.
• Assistant Examiner(s): STAFIRA, MICHAEL PATRICK
• Application Number:
  US09/285,335
• Time in Patent Office: 655 Days
• Field of Search: 356/337, 356/338, 356/339
• 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 2030/625 by measuring reference material, e.g. carrier without sample
• 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 30/60 : Construction of the column
• 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 33/442 : Resins; Plastics
• CPC Class Codes: G01N 35/085 : Flow Injection Analysis
• CPC Class Codes: G01N 35/1097 : characterised by the valves valves in general F16K

Abstract

Rapid characterization and screening of polymer samples to determine average molecular weight, molecular weight distribution and other properties is disclosed. Rapid flow characterization systems and methods, including liquid chromatography and flow-injection analysis systems and methods are preferably employed. High throughput, automated sampling systems and methods, high-temperature characterization systems and methods, and rapid, indirect calibration compositions and methods are also disclosed. The described methods, systems, and devices have primary applications in combinatorial polymer research and in industrial process control.

Claims

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

providing a library comprising four or more different non-biological polymer samples,

serially injecting the four or more non-biological polymer samples into a mobile-phase of a continuous-flow detector in a flow-injection analysis system, and

detecting a property of the injected samples or of components thereof with the continuous-flow detector.

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

3. The method of claim 1 wherein the four or more polymer samples are members of a combination library of polymerization product mixtures.

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

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

6. The method of claim 1 wherein the four or more polymer samples are 8 or more polymer samples.

7. The method of claim 1 wherein the four or more polymer samples are 40 or more polymer samples.

8. The method of claim 1 wherein the four or more polymer samples are 80 or more polymer samples.

9. The method of claim 1 wherein the four or more polymer samples are 150 or more polymer samples.

10. The method of claim 1 wherein the four or more polymer samples are 400 or more polymer samples.

11. The method of claim 1 wherein the four or more polymer samples are 1000 or more polymer samples.

12. The method of claim 1 wherein the four or more polymer samples are 2000 or more polymer samples.

13. The method of claim 1 wherein the four or more polymer samples are 5000 or more polymer samples.

14. The method of claim 1 wherein the property of the injected samples are detected at an average sample-throughput of not more than about 10 minutes per sample.

15. The method of claim 1 wherein the property of the injected samples are detected at an average sample-throughput of not more than about 4 minutes per sample.

16. The method of claim 1 wherein the property of the injected samples are detected at an average sample-throughput of not more than about 2 minutes per sample.

17. The method of claim 1 wherein the property of the injected samples are detected at an average sample-throughput of not more than about 1 minutes per sample.

18. The method of claim 1 wherein the property of the injected samples are detected at an average sample-throughput of not more than about 40 seconds per sample.

19. The method of claim 1 wherein the property of the injected samples are detected at an average sample-throughput of not more than about 20 seconds per sample.

20. The method of claim 1 wherein the property of the injected samples are detected at an average sample-throughput of not more than about 10 seconds per sample.

21. The method of claim 1 wherein the property of the injected samples are detected at an average sample-throughput of not more than about 5 seconds per sample.

22. The method of claim 1 wherein the polymer samples are characterized by a method comprising

withdrawing a first polymer sample from a first sample container,

injecting at least a portion of the withdrawn first sample into the mobile phase of the continuous-flow detector at a first injection time, t_FII1,

detecting the property of the injected first sample,

withdrawing a second polymer sample from a second sample container,

injecting at least a portion of the withdrawn second sample into the mobile phase of the continuous-flow detector at a second injection time, t_FII2, the difference in time, t_FII2−

t_FII1, being not more than about 10 minutes,

detecting the property of the injected second sample, and

repeating each of the aforementioned steps at least once.

80. The method of claim 1 wherein the library comprises the four or more different non-biological polymer samples on a common substrate.

81. The method of claim 1 wherein each of the four or more polymer samples of the library resides in a sample container, the method further comprising withdrawing each of the four or more polymer samples from its sample container.

82. The method of claim 81 wherein the sample containers are formed in, at or on a common substrate.

83. The method of claim 81 wherein the sample containers are reaction vessels.

84. The method of claim 81 wherein the sample containers are glass-lined reaction vessels.

85. The method of claim 1 wherein the library comprises twenty or more polymer samples and at least about 50% of the polymer samples included in the library are different from each other.

86. The method of claim 1 wherein the library comprises twenty or more polymer samples and at least 75% of the polymer samples included in the library are different from each other.

87. The method of claim 1 wherein the library comprises twenty or more polymer samples and at least 90% of the polymer samples included in the library are different from each other.

88. The method of claim 1 wherein the four or more polymer samples are polymerization product mixtures resulting from polymerization reactions that are varied with respect to a factor affecting polymerization.

89. The method of claim 1 wherein the four or more polymer samples are polymerization product mixtures resulting from polymerization reactions that are varied with respect to reactant materials, catalysts, catalyst precursors, initiators, additives or the reactive amounts thereof.

90. The method of claim 1 wherein the four or more polymer samples are polymerization product mixtures resulting from polymerization reactions that are varied with respect to reaction conditions.

91. The method of claim 1 wherein the four or more polymer samples are polymerization product mixtures resulting from synthesis in a parallel polymerization reaction.

92. The method of claim 1 wherein the polymer sample is a polymerization product mixture that is untreated or pretreated only with one or more steps selected from the group consisting of non-chromatographic separation, dilution, mixing, and redissolution.

93. The method of claim 1 the flow-injection analysis system comprises a pump for providing flow of a mobile phase from a mobile-phase fluid source to a flow-through detector, an injection port, and optionally an injection valve, the injection port and optional injection valve being adaptable for fluid communication with the mobile phase for injecting the polymer samples into the mobile phase, the flow-through detector being adapted to detect a property of the polymer samples or a component thereof.

23. 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 continuous-flow detector in a flow-injection analysis system, and

detecting a property of the injected samples or of components thereof with the continuous-flow detector at an average sample-throughput of not more than about 30 seconds minutes per sample.

24. A method for characterizing a non-biological polymer sample, the method comprising

injecting a non-biological polymer sample into a mobile phase of a continuous-flow light-scattering detector,

advancing the injected sample toward a detection cavity of the detector, the sample-containing mobile phase having an advancing flowrate, V_ADVANCE, while the injected sample is advanced toward the detection cavity,

reducing the flowrate of the sample-containing mobile phase to a detection flowrate, V_DETECT,

detecting light scattered from the injected sample or from a component thereof in the detection cavity of the detector while the mobile-phase flowrate is reduced to the detection flowrate, V_DETECT, and

flushing the sample from the detection cavity after detecting the scattered light.

25. The method of claim 24 further comprising

increasing the flowrate of the sample-containing mobile phase from V_DETECT to a passing flowrate, V_PASS, after detecting the scattered light, and

passing the flushed sample away from the detection cavity of the light-scattering detector at the passing flowrate, V_PASS.

26. The method of claim 25 wherein the passing flowrate, V_PASS, is substantially the same as the advancing flowrate, V_ADVANCE.

27. The method of claim 24 wherein the polymer sample is a first polymer sample, the method further comprising

injecting a second polymer sample into the mobile phase of the continuous-flow light-scattering detector.

28. The method of claim 27 wherein the second polymer sample is injected while the first polymer sample is passed away from the detection cavity of the light-scattering detector.

29. The method of claim 27 wherein the second polymer sample is injected while the light scattered from the first polymer sample is detected.

30. The method of claim 27 wherein the second polymer sample is injected while the first polymer sample is advanced toward the detection cavity of the light-scattering detector.

31. The method of claim 24 wherein the advancing flowrate, V_ADVANCE, is greater than the detection flowrate, V_DETECT, by a factor of at least about two.

32. The method of claim 24 wherein the advancing flowrate, V_ADVANCE, is greater than the detection flowrate, V_DETECT, by a factor of at least about five.

33. The method of claim 24 wherein the advancing flowrate, V_ADVANCE, is greater than the detection flowrate, V_DETECT, by a factor of at least about ten.

34. The method of claim 24 wherein the advancing flowrate, V_ADVANCE, is greater than the detection flowrate, V_DETECT, by a factor of at least about ten, the method further comprising

increasing the flowrate of the sample containing mobile phase to a passing flowrate, V_PASS, that is about the same as the advancing flowrate, V_ADVANCE, after detecting the scattered light, and

passing the flushed sample away from the detection cavity of the light-scattering detector at the passing flowrate, V_PASS.

35. The method of claim 24 wherein the advancing flowrate, V_ADVANCE, ranges from about 1 ml/min to about 25 ml/min.

36. The method of claim 24 wherein the detection flowrate, V_DETECT, ranges from about zero to about 1 ml/min.

37. The method of claim 24 wherein the advancing flowrate, V_ADVANCE, ranges from about 1 ml/min to about 5 ml/min and the detection flowrate, V_DETECT, ranges from about 0.1 ml/min to about 0.5 ml/min.

38. The method of claim 24 wherein the advancing flowrate, V_ADVANCE, is reduced to the detection flowrate, V_DETECT, when a leading edge of the polymer sample enters the detection cavity of the light-scattering detector, and the detection flowrate, V_DETECT, is maintained for a period of time ranging from about 1 second to about 60 seconds.

39. The method of claim 24 wherein the polymer sample is selected from the group consisting of a polymer solution, a polymer emulsion, and a polymer dispersion.

40. The method of claim 24 wherein the polymer sample comprises a polymer component having a particle diameter ranging from about 1 nm to about 300 nm.

41. The method of claim 24 wherein the polymer sample comprises a polymer component, a monomer component, and a continuous fluid phase.

42. The method of claim 24 wherein the polymer sample comprises a copolymer component, a first comonomer component, a second comonomer component, and a continuous fluid phase.

43. The method of claim 24 wherein the light-scattering detector is a static-light-scattering detector or a dynamic-light-scattering detector.

44. The method of claim 24 further comprising determining a property of interest from the detected scattered light.

45. The method of claim 44 wherein the determined property is selected from the group consisting of hydrodynamic radius, radius of gyration, and molecular weight.

46. The method of claim 44 wherein the determined property is an approximate molecular weight.

47. The method of claim 44 wherein the determined property is a weight-average molecular weight.

48. The method of claim 24 further comprising filtering the polymer sample before detecting the scattered light.

49. The method of claim 24 further comprising chromatographically separating the polymer sample before detecting the scattered light.

50. A method for characterizing a non-biological polymer sample, the method comprising

injecting a non-biological polymer sample into a mobile-phase of a continuous-flow light-scattering detector,

detecting light scattered from the injected sample or from a component thereof in a detection cavity of the detector, the sample-containing mobile phase having a detection flowrate, V_DETECT, while the scattered light is detected,

flushing the sample from the detection cavity after detecting the scattered light,

increasing the flowrate of the sample-containing mobile phase to a passing flowrate, V_PASS, after detecting the scattered light, and

passing the flushed sample away from the detection cavity of the detector at the increased higher flowrate, V_PASS.

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

serially injecting a plurality of non-biological polymer samples into a mobile phase of a continuous-flow light-scattering detector,

advancing the injected samples toward a detection cavity of the detector,

detecting light scattered from the injected samples or from a component thereof in the detection cavity,

flushing the samples from the detection cavity after detecting the scattered light,

passing the flushed sample away from the detection cavity, and

controlling the flow-rates of the samples during the steps of injecting, advancing, detecting, flushing or passing such that the average sample throughput is not more than about 60 seconds per sample.

52. The method of claim 51 wherein the plurality of polymer samples are a library of polymerization product mixtures.

53. The method of claim 51 wherein the average sample throughput is not more than about 50 seconds per sample.

54. The method of claim 51 wherein the average sample throughput is not more than about 40 seconds per sample.

55. The method of claim 51 wherein the average sample throughput is not more than about 30 seconds per sample.

56. The method of claim 51 wherein the average sample throughput is not more than about 20 seconds per sample.

57. The method of claim 51 wherein the average sample throughput is not more than about 10 seconds per sample.

58. The method of claim 51 wherein the average sample throughput is not more than about 5 seconds per sample.

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

(a) withdrawing a non-biological polymer sample from a sample container,

(b) injecting the polymer sample into a mobile-phase of a continuous-flow light-scattering detector while the mobile phase has an advancing flowrate, V_ADVANCE,

(c) advancing the injected first sample toward a detection cavity of the detector while maintaining the flowrate of the mobile phase at the advancing flowrate, V_ADVANCE,

(d) reducing the flowrate of the mobile-phase to a detection flowrate, V_DETECT,

(e) detecting light scattered from sample or from a component thereof in the detection cavity of the detector while the mobile-phase flowrate is at the reduced detection flowrate, V_DETECT,

(f) flushing the first sample from the detection cavity after detecting the scattered light,

(g) increasing the flowrate of the mobile-phase to a passing flowrate, V_PASS that is substantially the same as advancing flowrate, V_ADVANCE, after detecting the scattered light,

(h) passing the flushed sample away from the detection cavity of the detector while maintaining the flowrate of the mobile phase at the passing flowrate, V_PASS, and

(i) repeating steps (a) through (h) for a plurality of non-biological polymer samples.

60. The method of claim 59 wherein the advancing flowrate, V_ADVANCE, ranges from about 1 ml/min to about 5 ml/min, and the detection flowrate, V_DETECT, ranges from about 0.1 ml/min to about 0.5 nl/min.

61. The method of claim 59 wherein the advancing flow rate of the mobile phase, V_ADVANCE, is reduced to the detection flowrate, V_DETECT, when a leading edge of the sample enters the detection cavity of the detector, and the detection flowrate, V_DETECT, is maintained for a detecting period ranging from about 1 second to about 60 seconds.

62. The method of claim 61 wherein the detecting period ranges from about 5 seconds to about 20 seconds.

63. The method of claim 61 wherein the detecting period ranges from about 7 seconds to about 15 seconds.

64. The method of claim 61 wherein the detecting period ranges from about 10 seconds to about 12 seconds.

65. The method of claim 59 wherein the average sample throughput is not more than about 40 seconds per sample.

66. The method of claim 59 wherein the average sample throughput is not more than about 20 seconds per sample.

67. The method of claim 59 wherein the average sample throughput is not more than about 10 seconds per sample.

68. The method of claim 59 wherein the average sample throughput is not more than about 5 seconds per sample.

69. The method of claim 59 wherein the polymer sample comprises a polymer component having a particle size ranging from about 1 nm to about 500 nm in diameter.

70. A method for characterizing a polymer sample, the method comprising

injecting a polymer sample into a mobile phase of a continuous-flow detector om a flow-injection analysis system,

detecting a property of the injected sample or of one or more components thereof with the continuous-flow detector, and

maintaining the sample at a temperature of not less than about 75°

C. during a period of time including from when the sample is injected into the mobile phase of the continuous-flow detector to when the property of the injected samples or of a component thereof is detected.

71. The method of claim 70 wherein the sample is maintained at a temperature of not less than about 100°

C. during the period from when the sample is injected into the mobile phase to when the property of the injected samples or of a component thereof is detected.

72. The method of claim 70 wherein the sample is maintained at a temperature of not less than about 125°

C. during the period from when the sample is injected into the mobile phase to when the property of the injected samples or of a component thereof is detected.

73. The method of claim 70 wherein the sample is maintained at a temperature of not less than about 150°

C. during the period from when the sample is injected into the mobile phase to when the property of the injected samples or of a component thereof is detected.

74. In a continuous-flow light-scattering detection system comprising a light-scattering detector having a detection cavity, the detection cavity having an inlet port and an outlet port through which a sample-containing mobile phase can flow, a mobile-phase fluid source in fluid communication with the inlet port of the detection cavity, a pump for providing flow of the mobile phase from the source to the detection cavity, and an injection port in fluid communication with the mobile phase for injecting a sample into the mobile phase of the continuous-flow light-scattering detector, the improvement comprising

a detector for indicating the position of an injected sample relative to the detection cavity,

a flow-control element for controlling the flowrate of the mobile phase, and

a controller in communication with the detector and with the flow-control element.

75. The continuous-flow light-scattering detection system of claim 74 wherein the light-scattering detector is a static light-scattering detector.

76. The continuous-flow light-scattering detection system of claim 74 wherein the light-scattering detector is dynamic light-scattering detector.

77. The continuous-flow light-scattering detection system of claim 74 wherein the detector for indicating the position of an injected sample is selected from the group consisting of a static light-scattering detector, a dynamic light-scattering detector, an evaporative light-scattering detector and a refractive index detector.

78. The continuous-flow light-scattering detection system of claim 74 wherein the detector for indicating the position of an injected sample is a static light-scattering detector.

79. The continuous-flow light-scattering detection system of claim 74 wherein the light-scattering detector is a dynamic light-scattering detector and the detector for indicating the position of an injected sample is a static light-scattering detector.