Apparatus and method for multiple channel high throughput purification

• US 6,309,541 B1
• Filed: 10/29/1999
• Issued: 10/30/2001
• Est. Priority Date: 10/29/1999
• Status: Expired due to Fees

• Current Assignee: Romaine R. Maiefski
• Original Assignee: Ontogen Corporation (Infinity Pharmaceuticals, Inc.)
• Inventors: Ripka, William C., Maiefski, Romaine, Krakover, Jonathan D., Wendell, Don
• Primary Examiner(s): Therkorn, Ernest G.
• Application Number:
  US09/430,194
• Time in Patent Office: 732 Days
• Field of Search: 210/635, 210/656, 210/659, 210/143, 210/198.2, 95/828.6, 961/01, 961/04, 422/70, 436/161
• US Class Current: 210/198.2
• CPC Class Codes: B01D 15/08 Selective adsorption, e.g. chromatography
• CPC Class Codes: B01D 15/1885 placed in parallel
• CPC Class Codes: B01D 15/40 using supercritical fluid as mobile phase or eluent
• CPC Class Codes: B01J 2219/00759 Purification of compounds synthesised
• CPC Class Codes: G01N 30/02 Column chromatography
• CPC Class Codes: G01N 30/24 Automatic injection systems
• CPC Class Codes: G01N 30/466 with separation columns in parallel
• CPC Class Codes: G01N 30/6004 end pieces
• CPC Class Codes: G01N 30/6052 body
• CPC Class Codes: G01N 30/82 Automatic means therefor

Abstract

A multiple channel high throughput purification system for purifying a plurality of samples, preferably four or more samples from a chemical library. The high throughput purification uses chromatography, and more preferably, super critical fluid chromatography. Four parallel channels are provided in this system and coupled to a common analyzer and computer. The four channels direct the selected sample flow through a separator, such as an SFC column, a detector, such as a UV detector, to detect peaks within the sample flow, and a micro sample valve that splits a sampling of the flow to an analyzer, such as a mass spectrometer. The system also utilizes unique back pressure regulator assemblies and pressure relief assemblies to maintain a selected pressure within the purification channel. While the sample flow continues, the mass spectrometer simultaneously analyzes the sampling to determine if a target compound is within the sample portion. A fraction collection valve directs sample portions to one of two fraction collectors such as a microtiter plate. The purified target compounds are collected in one microtiter plate and the other non-desirable peaks are collected in a second microtiter plate in corresponding wells. In the supercritical fluid chromatography purification system, an expansion chamber is provided to condense the vaporous sample flow before the purified compounds are added to the particular well of the microtiter plate. A fraction collection assembly is used that automates the use of disposable expansion chambers for depositing the samples in the microtiter plates.

Claims

1. A multiple channel, high throughput supercritical fluid chromatographic purification system for substantially simultaneously purifying multiple samples from a chemical library, each of the samples being separable into first and second components comprising:

a sample analyzer that analyzes selected sample characteristics;

a first purification channel coupled to the sample analyzer, the first purification channel including;

a first chromatographic sample separation device positioned to separate a first sample flow into first and second sample components;

a first detector positioned to detect the first and second components in the first sample flow;

a first flow diverting device moveable to direct a sampling of the first sample component to the analyzer and the remainder of the first sample portion flows along a first flow path away from the diverting first flow device;

a first collector positioned to receive at least a portion of the first or second sample component of the first sample the sample analyzer identified as having selected sample characteristics;

a second collector positioned to receive remaining components of the first sample not having the selected sample characteristics; and

a second purification channel coupled to the sample analyzer, the second purification channel including;

a second chromatographic separation device positioned to receive a second sample flow for separation into the first and second components of the second sample flow;

a second detector positioned to detect the first and second components of the second sample flow;

a second flow diverting device moveable to direct a sampling of the first or second components to the analyzer and a remainder of the second sample portion flows along a second flow path away from the flow diverting device;

a third collector positioned to receive at least a portion of the first or second sample components of the second sample having the selected sample characteristics; and

a fourth collector positioned to receive remaining components of the second sample not having the selected sample characteristics.

2. The system of claim 1, further comprising a third purification channel coupled to the sample analyzer, the third purification channel including:

a third chromatographic separation device positioned to receive a third sample flow for separation into the first and second components of the third sample flow;

a third detector positioned to detect the first and second component portions of the third sample flow;

a third flow diverting device movable to direct a sampling of the first or second components of the third sample flow to the analyzer and a remainder the third sample portion flows along a third flow path away from the third flow diverting device;

the first collector being positioned to receive the first or second components of the third sample flow having the selected sample characteristics;

the second collector being positioned to receive the remaining components of the third sample flow not having the selected sample characteristics; and

a fourth purification channel coupled to the common sample analyzer, the fourth purification channel including;

a fourth chromatographic separation device positioned to receive a fourth sample flow for separation into the first and second components of the fourth sample flow;

a fourth detector positioned to receive the first and second component of the fourth sample;

a fourth flow diverting device movable to direct a sampling of the first or second components of the fourth sample flow to the analyzer and a remainder of the fourth sample portion flows along a fourth flow path away from the flow diverting device;

the first collector being positioned to receive the first or second components of the fourth sample having the selected sample characteristics; and

the second collector positioned to receive the remaining components of the fourth sample not having the sample characteristics.

3. The purification system of claim 1 wherein the sample analyzer is a mass spectrometer.

4. The purification system of claim 1 wherein at least one of the four separation devices is a chromatography column.

5. The purification system of claim 1 wherein at least one of the four detectors is a UV detector.

6. The purification system of claim 1 wherein at least one of the first and second flow diverting devices is a microsample valve in fluid communication with the analyzer and movable between open and closed positions to allow the sampling of the respective sample flows to pass to the analyzer.

7. The purification system of claim 1 wherein the sample is vaporous as it moves through the first purification channel, and further comprising an expansion chamber positioned to receive and condense the vaporous sample to a liquid before the sample is received by the first or second collectors.

8. The purification system of claim 1, further comprising a pressure regulator positioned to receive the first sample flow and adjust a pressure of the first sample flow in the first purification channel upstream of the first flow diverting device.

9. The purification system of claim 8 wherein the pressure regulator has a heater portion that heats at least a portion of the first sample flow.

10. The purification system of claim 1 further comprises a pressure relief valve position downstream of the first flow diverting device.

11. The purification system of claim 1 wherein each sample is vaporous as it moves through its respective purification channel, and further comprising an expansion chamber positionable to receive and condense the vaporous respective sample to a liquid before the respective sample is received by the first or second collectors.

12. The purification system of claim 1, further comprising a sample holder having a plurality of sample receptacles including a sample receptacle, each sample receptacle being in a predetermined location relative to the other sample receptacles, and the collector has a plurality of collection wells, each collection well having a predetermined location relative to the other collection well, and the predetermined location of each sample receptacle corresponds to the predetermined location of a respective one of the collection wells.

13. A multiple channel, high throughput purification system for substantially simultaneously purifying at least two samples from a chemical library, comprising:

a controller;

a sample analyzer coupled to the controller, the analyzer being configured to determine whether the first sample has selected sample characteristics;

at least two purification channels coupled to the common sample analyzer, each purification channel including;

a separation device positioned to receive a sample flow containing the sample and to separate the sample into first and second sample components spaced apart from each other in the first sample flow;

a detector coupled to the separation device, the detector being positioned to receive the sample flow from the separation device, the detector configured to detect at least the sample component within the first sample flow;

a flow sampling device positioned to receive the sample flow from the detector, the flow sampling device being moveable between open and closed positions, in the open position the flow sampling device directs a sampling of the sample component to the analyzer and a remainder of the first sample flows along a flow path past the flow splitting device, and in the closed position the device blocks the sample flow from passing to the analyzer;

a flow directing valve in fluid communication with the flow path and positioned to receive the sample, the flow directing valve being movable to a first position to direct the sample portion in a first direction if the analyzer has determined that the sample component has the selected sample characteristics, and the flow directing valve being movable to a second position to direct the sample portion in a second direction if the analyzer has determined that the sample component does not have the first selected sample characteristics;

a first collector positioned to receive the sample components that have the selected sample characteristics from the flow directing devices when the flow directing devices are in the first position; and

a second collector and positioned to receive the sample components that do not have the selected sample characteristics when the first flow directing devices are in the second position.

14. The purification system of claim 13 wherein the common sample analyzer is a mass spectrometer.

15. The purification system of claim 13 wherein at least one of the two separation devices is a chromatography column.

16. The purification system of claim 13 wherein at least one of the two separation devices is a supercritical fluid chromatography column.

17. The purification system of claim 13 wherein at least one of the two detectors is a UV detector.

18. The purification system of claim 13 wherein at least one of the two flow sampling devices is a microsample valve.

19. The purification system of claim 13 wherein the sample flow is vaporous as it moves through the purification channel, and further comprising an expansion chamber positioned to receive the vaporous sample flow and condense the selected component flow to a liquid before it is received by the first or second collector.

20. The purification system of claim 19 wherein the expansion chamber is sized to receive the vaporous sample component herein and to condense the vaporous first sample component along side walls of the expansion chamber.

21. The purification system of claim 13 wherein the second sample flow is vaporous as it moves through the second purification channel, and further comprising an expansion chamber positioned to receive the vaporous second sample flow and to condense the second sample to a liquid before the second sample is received by the third or fourth collector.

22. The purification system of claim 13, further comprising a sample holder for each channel having a plurality of sample receptacles including a first sample receptacle, each sample receptacle being in a predetermined location relative to the other sample receptacles, and the first collector is in a collection assembly having a plurality of collectors therein, each collector having a predetermined location relative to the other collectors, and the predetermined location of the first sample receptacle in the sample holder corresponds to the predetermined location of the first collector.

23. The purification system of claim 13, further comprising a controller operatively connected to the sample analyzer, four flow splitting valves and the four flow directing valves to control the sample flows in response to analysis results from the analyzer regarding the components from each of the channels.

24. A multiple channel, high throughput purification system for substantially simultaneously purifying at least two samples from a chemical library, comprising:

a sample analyzer configured to determine whether a sample portion passing therethrough has selected sample characteristics;

at least two purification channels coupled to the common sample analyzer and configured to simultaneously carry a respective sample flow, each purification channel including;

a sample separation device configured to separate a selected sample into first and second sample components spaced apart from each other in the respective sample flow;

a detector coupled to the sample separation device, the detector being configured to detect at least one sample component within the respective sample flow;

a flow sampling device positioned to receive the respective sample flow from the detector, the flow sampling device being moveable to direct a sampling of the sample component to the analyzer and a remainder of the respective sample flow continues along the respective flow path;

a first collector positioned to receive the sample components that have the selected sample characteristics from the flow directing devices when the flow directing devices are in the first position; and

a second collector and positioned to receive the sample components that do not have the selected sample characteristics when the first flow directing devices are in the second position.

25. The system of claim 24 wherein each purification channel includes a flow directing valve in fluid communication with the respective flow path and positioned to receive the sample portion in the respective sample flow, the flow directing valve being movable to a first position to direct the sample portion in a first direction if the analyzer has determined that the sample component has the selected sample characteristics, and the flow directing valve being movable to a second position to direct the sample portion in a second direction if the analyzer has determined that the sample component does not have the first selected sample characteristics.

26. The system of claim 25 wherein the flow directing valve is positioned to direct the sample portion to the first collector when the flow directing valve is in the first position and to direct the sample portion to the second collector when the flow directing valve is in the second position.

27. The system of claim 24 wherein the system includes four purification channels.

28. The system of claim 24, further comprising a controller coupled to the analyzer.

29. The system of claim 24 wherein the separation device in each purification channel is positioned to receive the respective sample flow before the sample flow reaches the detector and the flow sampling device.