Patent Description:
The invention relates generally to liquid chromatography systems and more particularly, to systems and methods for performing multidimensional liquid chromatography.

Multidimensional liquid chromatography (MDLC) offers a powerful solution to the most challenging chemical separation problems. However, there are a series of limitations which prevent broad deployment and acceptance of this technology. For example, a system configured for MDLC is only able to perform MDLC and replumbing would be required to switch between MDLC and single dimensional separation.

Affinity selection mass spectrometry (automated ligand identification system) is one example of MDLC. Affinity selection mass spectrometry is a technique used to identify the most effective protein-binding candidate amongst a library of small molecules. It separates the bound small molecule - protein complex on a primary size exclusion dimension. The complex is heart-cut and modulated onto a secondary, denaturing reversed phase dimension where is bound small molecule is separated from the protein, then passed to a mass spectrometer for quantitation and identification.

Known systems for performing affinity selection mass spectrometry or other multidimensional processes are not known to be readily and easily reconfigurable to be able to perform single dimensional separation. Therefore, a new system capable of performing both single and multidimensional chromatography with ease of switching therebetween and having no replumbing required would be well received in the art.

<CIT> discloses chromatography systems that include a microfluidic device, and methods for using them. <CIT> discloses a multiple column chromatographic system and methods of use. <CIT> discloses branching off a fluidic sample with low influence on a source flow path. <CIT> discloses a fluid separation method and a fluid separation apparatus.

The present invention provides a system capable of performing both single and multidimensional liquid chromatography comprises: a solvent delivery system; a first dimension column path configured to perform a separation process in a first dimension; a second dimension column path configured to perform a separation process in a second dimension; and a valve system; a sample injection system fluidically connected to the valve system. The valve system is configured to direct flow from the sample injection system to the first dimension column path when the valve system is in a first position. Further, the valve system is configured to direct flow from the sample injection system to the second dimension column path without the flow path flowing through the first dimension column path in the chromatography system when the valve system is in a second position.

Additionally or alternatively, the system includes a first detector located downstream from the first dimension column path, wherein the first detector is not a mass spectrometer; and a second detector located downstream from the second dimension column path, wherein the second detector is a mass spectrometer.

The solvent delivery system further includes: a first solvent delivery subsystem having a first pump, wherein the first solvent delivery subsystem is directly fluidically connected to a first valve of the valve system; and a second solvent delivery subsystem having a second pump, wherein the second solvent delivery subsystem is directly fluidically connected to a second valve of the valve system.

Additionally or alternatively, the valve system is configured direct flow from the sample injection system to the first dimension column path and store a portion of the flow in a storage loop, wherein the valve system is configured to further flow the portion of the flow through the second dimension column path.

Additionally or alternatively, the first valve is switchable from a first valve first position to a first valve second position, wherein in the first valve first position flow is directed from the first solvent delivery subsystem to the sample injection system, and wherein in the first valve second position flow is directed from the second solvent delivery subsystem to the sample injection system.

Additionally or alternatively, the system includes a sample storage loop fluidically connected to the second valve of the valve system.

Additionally or alternatively, the second valve is switchable from a second valve first position to a second valve second position, wherein in the second valve first position flow from the first solvent delivery subsystem is directed from the first detector to the sample storage loop and a path leading to a downstream waste, and wherein in the second valve second position fluid from the first solvent delivery subsystem is directed from the first detector directly to the path leading to the downstream waste while bypassing the sample storage loop.

Additionally or alternatively, in the second valve first position flow from the second solvent delivery subsystem is directed through the sample storage loop, to the first valve and to the second dimension column path, wherein in the second valve second position flow from the second solvent delivery subsystem is directed directly to the first valve and the second dimension column path while bypassing the sample storage loop.

Additionally or alternatively, the first dimension column path includes a size exclusion chromatography column, and wherein the second dimension column path includes a reversed phase liquid chromatography column.

The present invention provides a method of dimensional selection for a chromatography system comprises: using a valve system of the chromatography system to direct flow from a sample injection system to a first dimension column path and into a second dimension column path, wherein the first dimension column path is configured to perform a first separation process in a first dimension, and wherein the second dimension column path is configured to perform a second separation process in a second dimension; and switching positions of the valve system to direct flow from the sample injection system to the second dimension column path without the flow path flowing through the first dimension column path in the chromatography system.

Additionally or alternatively, the chromatography system includes: a first detector located downstream from the first dimension column path, wherein the first detector is not a mass spectrometer; and a second detector located downstream from the second dimension column path, wherein the second detector is a mass spectrometer.

The valve system includes a first valve directly fluidically connected to a first solvent delivery subsystem, and wherein the valve system includes a second valve directly fluidically connected to a second solvent delivery subsystem. The method may further include: switching the first valve from a first valve first position to a first valve second position, wherein in the first valve first position flow is directed from the first solvent delivery subsystem to the sample injection system, and wherein in the first valve second position flow is directed from the second solvent delivery subsystem to the sample injection system.

Additionally or alternatively, the method further includes switching the second valve from a second valve first position to a second valve second position, wherein in the second valve first position flow from the first solvent delivery subsystem is directed from a first detector to a sample storage loop and then to a path leading to a downstream waste, and wherein in the second valve second position fluid from the first solvent delivery subsystem is directed from the first detector directly to the path leading to the downstream waste while bypassing the sample storage loop.

Additionally or alternatively, the method further includes directing flow from the second solvent delivery subsystem through the sample storage loop to the first valve and to the second dimension column path when the second valve is in the second valve first position; and directing flow from the second solvent delivery subsystem directly to the first valve and the second dimension column path while bypassing the sample storage loop when the second valve is in the second valve second position.

In another exemplary embodiment, disclosed but not independently claimed, a valve system for a liquid chromatography system comprises: a first valve; and a second valve fluidically connected to the first valve. The first and second valves are configured direct flow from a sample injection system to a first dimension column path when the valve system is in a first position. Further, the first and second valves configured to direct flow from the sample injection system to the second dimension column path without the flow path flowing through the first dimension column path in the chromatography system when the valve system is in a second position.

Additionally or alternatively, the first valve is switchable from a first valve first position to a first valve second position, wherein in the first valve first position flow is configured to be directed from a first solvent delivery subsystem to the sample injection system, and wherein in the first valve second position flow is configured to be directed from a second solvent delivery subsystem to the sample injection system.

Additionally or alternatively, the valve system includes a sample storage loop fluidically connected to the second valve of the valve system.

Additionally or alternatively, the second valve is switchable from a second valve first position to a second valve second position, wherein in the second valve first position flow from the first solvent delivery subsystem is directed to the sample storage loop, and wherein in the second valve second position fluid from the first solvent delivery subsystem is directed from the first detector directly to the path leading to the downstream waste while bypassing the sample storage loop.

Additionally or alternatively, the valve system includes the sample injection system fluidically connected to the first valve.

Reference in the specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the teaching.

The present teaching will now be described in more detail with reference to exemplary embodiments thereof as shown in the accompanying drawings. While the present teaching is described in conjunction with various embodiments and examples, it is not intended that the present teaching be limited to such embodiments. On the contrary, the present teaching encompasses various alternatives, modifications and equivalents, as will be appreciated by those of skill in the art. Those of ordinary skill having access to the teaching herein will recognize additional implementations, modifications and embodiments, as well as other fields of use, which are within the scope of the present disclosure as described herein.

Referring firstly to <FIG>, a prior art multidimensional liquid chromatography system <NUM> is depicted schematically. The system <NUM> includes a quaternary solvent manager (QSM) <NUM>, a flow through needle (FTN) <NUM>, a size exclusion chromatography (SEC) column <NUM>, a binary solvent manager (BSM) <NUM>, storage loop <NUM> coupled to a rotary shear valve <NUM>, a first optical detector <NUM>, a second optical detector <NUM>, a reverse phase liquid chromatography (RPLC) column <NUM>, and a mass spectrometer (MS) <NUM>. The system further includes a waste pathway <NUM> downstream from the second optical detector <NUM>.

In practice, fluid from the quaternary solvent manager (QSM) <NUM> receives an injection of a sample by the flow through needle (FTN) <NUM>, after which the sample and solvent enters the size exclusion chromatograph (SEC) column <NUM> followed by the first optical detector <NUM>. At first, the flow may flow through the rotary shear valve <NUM> and into the second optical detector <NUM> and then proceed to the waste pathway <NUM>. Once the system, as detected by the first optical detector <NUM>, determines that a particular cut of the flow is needed for a second dimension separation process, the rotary shear valve <NUM> is rotated such that flow from the first optical detector <NUM> flows through the storage loop <NUM>. When the proper fluid is accumulated in the storage loop <NUM>, the binary solvent manager <NUM> is activated, and pumps solvent through the rotary shear valve <NUM> and into the storage loop <NUM>. At this point, the sample stored in the storage loop <NUM> will proceed through the rotary sear valve <NUM> and to the reverse phase liquid chromatography (RPLC) column for processing in a reverse phase dimension and finally to the mass spectrometer (MS) <NUM> for final detection in this dimension.

The above-described system is only operable for performing multidimensional liquid chromatography. Replumbing would be required in order to change the system <NUM> into a system configured for a single dimension separation process using the mass spectrometer.

<FIG> depicts a graphical depiction <NUM> of a separation process which separates small molecules bound to a protein, whereby the separated bound small molecules can be heart-cut and modulated onto a secondary dimension of separation, in accordance with one embodiment. The system capable of performing both single and multidimensional liquid chromatography described hereinbelow may be configured to perform a separation on a sample resulting in this detected plot over time. The separation shown in the graphical depiction <NUM> may be a first separation occurring in a first dimension in a two-stage multidimensional separation process. In particular, the separation may be a size exclusion separation in the first dimension. The system capable of performing both single and multidimensional liquid chromatography may thereafter be configured to store the portion of the fluid embodied by the first small peak <NUM> in a storage loop. Once stored in the storage loop, the system capable of performing both single and multidimensional liquid chromatography may move the stored portion containing the first small peak <NUM> and move this portion through a second separation process in a second dimension, such as a separation process that is mass spectrometry compatible. As shown, the graphical depiction <NUM> includes a curve <NUM> plotting absorbance units over time. A second larger and taller peak <NUM> exists after the first peak <NUM>. The first peak <NUM> may correspond to the protein and small molecule complex that will be subject to a second dimension of separation, while the second peak <NUM> may correspond to unbound small molecules in the sample.

<FIG> depicts a system <NUM> capable of performing both single and multidimensional liquid chromatography. Unlike the system <NUM>, the system <NUM> includes a valve system <NUM> that is configured to allow for the system to function as a single-dimensional separation or a MDLC system without re-plumbing or without altering the system fluidic structure. For example, the change between a single-dimensional separation to a MDLC system may be at the push of a button or the switching of a setting on a user interface or controller. The system <NUM> includes a solvent delivery system <NUM> that includes both a first solvent delivery subsystem <NUM> and a second solvent delivery subsystem <NUM>. The system <NUM> further includes a sample injection system <NUM>, a first dimension column such as a size exclusion chromatography (SEC) column <NUM>, a storage loop <NUM> coupled to the valve system <NUM>, a first optical detector <NUM>, a second optical detector <NUM>, a second dimension column such as reverse phase liquid chromatography (RPLC) column <NUM>, and a mass spectrometer (MS) <NUM>. The system further includes a waste pathway <NUM> downstream from the second optical detector <NUM>. Still further, the valve system <NUM> includes both a first valve <NUM> and a second valve <NUM>.

As shown, the valve system <NUM> is configured to direct flow from a sample injection system to a first dimension column path <NUM> when the valve system is in a first position, described in more detail herein below and shown in <FIG>. The first dimension column path <NUM> may be a fluidic pathway that provides a flow of fluid through a first column configured for separation in a first dimension, such as the SEC column <NUM> and an accompanying detector system, such as the optical detector <NUM>. Moreover, the valve system <NUM> is configured to direct flow from the sample injection system to a second dimension column path <NUM> without the flow path flowing through the first dimension column path <NUM> in the system <NUM> when the valve system <NUM> is in a second position, again as described in more detail herein below and shown in <FIG>. The second dimension column path <NUM> may be a fluidic pathway that provides a flow of fluid through a second column configured for separation in a second dimension, such as the RPLC column <NUM> and an accompanying detector system, such as the mass spectrometer <NUM>.

The solvent delivery system <NUM> is shown comprising two solvent delivery subsystems <NUM>, <NUM>. The solvent delivery subsystems <NUM>, <NUM> may each include a pump. The pumps may be binary, quaternary, or isocratic pumps, for example. The pumps may be inclusive within a solvent manager system that is fluidically connected to solvent containers in order to pump solvent from the solvent containers to the downstream separation system. Moreover, there may be embodiments where the solvent delivery system <NUM> includes more or less than two subsystems shown.

Further, the sample injection system may be a sample manger system that includes various functionality, depending on the embodiment. The sample injection system may comprise a flow through needle or other injection system. Moreover, the sample injection system may include an operator system configured to load and unload samples therein for separation and may further store samples awaiting processing or having already been processed.

While the system <NUM> is shown including one SEC column <NUM>, and one RPLC column <NUM>, other types of columns are contemplated. The mobile phase flowing through the SEC column <NUM> may not be compatible with mass spectrometry, while the mobile phase flowing through the RPLC column <NUM> may be mass spectrometry compatible. Thus, the system <NUM> includes a first column that separates a sample for optical detection and not a mass spectrometer, while a second column separates the sample via the mass spectrometer <NUM>. However, other embodiments are contemplated wherein the RPLC column <NUM> is replaced with any other type of column with a mobile phase that is mass spectrometer <NUM> compatible and the SEC column <NUM> is replaced with any other column with a mobile phase that is optical detection compatible. In other embodiments, the columns <NUM>, <NUM> may not be configured for optical detection and mass spectrometry, respectively. In other words, the columns <NUM>, <NUM> in combination may be configured for any multidimensional liquid chromatography application. The first column <NUM> may be any type of chromatography column configured to provide a separation in a first dimension, and the second column <NUM> may be any other type of chromatography column configured to provide a separation in a second dimension.

The embodiment shown further includes the storage loop <NUM>. The storage loop may be any appropriate volume storage loop. For example, in contemplated embodiments, the storage loop may be <NUM>µL. In other applications, the storage loop may be larger or smaller than <NUM>µL, depending on, for example, the amount of sample volume in a heart-cut MDLC application. Moreover, the storage loop may be replaced by a trapping column or a combination of a storage loop and a trapping column arranged in series.

The embodiment shown includes two optical detectors <NUM>, <NUM>. The first optical detector <NUM> is shown directly downstream from the SEC column <NUM>, while the second optical detector <NUM> is shown directly upstream from the waste pathway <NUM>. Other embodiments may only include a second detector downstream from the SEC column <NUM>, for example. The second detector <NUM> may be a failsafe or confirmation detector configured to confirm the accuracy of detection occurring at the first detector <NUM>. In some embodiments, the detectors <NUM>, <NUM> may be the same general type of optical detectors. In other embodiments, the detectors <NUM>, <NUM> may have different properties. For example, one may be a tunable UV-Visible (TUV) absorbance detector, while the other may be a photodiode array (PDA) detector.

The mass spectrometer <NUM> downstream from the RPLC column <NUM> may be any type of known mass spectrometer, such as a single quadrupole mass detector, a tandem quadrupole or triple quadrupole mass detector, a time of flight mass spectrometer, an ion mobility mass spectrometer, an ion trap mass spectrometer, or the like. In still other embodiments, the second dimension column path <NUM> may be configured for a second dimension of separation which is not mass spectrometry compatible. Examples of dimensions of separation include a hydrophilic interaction LC (HILIC), a hydrophobic interaction chromatography (HIC), precipitation-redistribution liquid chromatography (PRLC), affinity enrichment chromatography (affinity chromatography), ion exchange chromatography, normal phase liquid chromatography, supercritical fluid chromatography (SFC) or the like.

The valve system <NUM> is shown including the two valves <NUM>, <NUM>. While the valves <NUM>, <NUM> are each shown to be two position rotary shear valves which may be particularly advantageous in the application, other types of fluidic valve system capable of performing the functionality described herein may also be utilized. The rotary shear valves shown each include <NUM> ports for attaching to fluidic lines. One port for each of the two valves is utilized for a fluidic line connecting the two valves. The valve system <NUM> and in particular the two valves <NUM>, <NUM>, are fluidically connectable directly to each of the solvent delivery system <NUM> (and subsystems <NUM>, <NUM> thereof), the sample injection system <NUM>, the columns <NUM>, <NUM>, the detectors <NUM>, <NUM>, and the storage loop <NUM>.

Moreover, the valve system <NUM> may include a structural housing that includes fluidic ports for allowing the various fluidic pathways to connect to the valve system <NUM> in the schematic manner shown in <FIG> and <FIG>. Further, within the structural housing, the valve system <NUM> may include the storage loop <NUM>. Still further, the valve system <NUM> may be an inclusive system which includes the functionality of the sample injection system <NUM> in some embodiments. Thus, the valve system <NUM> may be incorporated into a greater sample manager system that includes a sample injection system such as a flow through needle, along with the valves <NUM>, <NUM>, and the storage loop <NUM>.

<FIG> depicts a perspective view of a system stacking configuration for the system <NUM> of <FIG>, in accordance with one embodiment. The stacking configuration includes the mass spectrometer <NUM> set next to a dual stacked system. The stacking configuration includes a first set of solvent bottles <NUM> and a second set of solvent bottles <NUM>. The solvent bottles <NUM>, <NUM> may be in fluidic communication with a first pump system <NUM> and a second pump system <NUM>. A sample manager <NUM> includes the sample injection system <NUM>. A column management system <NUM> includes the size exclusion chromatography (SEC) column <NUM> and the reverse phase liquid chromatography (RPLC) column <NUM> therein (not shown). The first optical detector <NUM> and the second optical detector <NUM> are also shown in the system stacking configuration. In one embodiment, the first optical detector <NUM> may be a tunable UV detector, while the second optical detector <NUM> may be a photodiode array (PDA) detector.

<FIG> depicts the system <NUM> of <FIG> having the valve system <NUM> in a first position and receiving a flow of fluid from the first solvent delivery subsystem <NUM>, in accordance with one embodiment. As shown in this embodiment, the valve system <NUM> is in a first position whereby the first valve <NUM> is in position <NUM> and the second valve is in position <NUM>. In this position, to start a multidimensional separation process, the first solvent delivery subsystem <NUM> is fluidically connected to the first valve <NUM> of the valve system <NUM> and provides flow (i.e. via a pump or pump system) to the first valve <NUM> from a solvent reservoir or bottle. The flow of solvent is directed through the sample injection system <NUM> whereby the sample is injected into the flow of solvent. The first valve <NUM> then directs the flow to the SEC column <NUM> and the first detector <NUM>. Thereafter, the flow is flow through the second valve <NUM> which directs the flow to the second detector <NUM> and thereafter to a waste pathway <NUM>.

<FIG> depicts the system of <FIG> having the valve system <NUM> in a second position and receiving a flow of fluid from the first solvent delivery subsystem <NUM>, in accordance with one embodiment. As shown in this embodiment, the valve system <NUM> is in a second position whereby the first valve <NUM> is in position <NUM> and the second valve is in position <NUM>. In this position, relative to the position shown in <FIG>, the second valve has been rotated to redirect flow through a storage loop <NUM> prior to flowing through the pathway to the second detector <NUM> and the waste pathway <NUM>. Switching the valve system <NUM> from the first position (shown in <FIG>) to the second position (shown in <FIG>) may be considered the second step in a multidimensional separation process. This step may occur when a technician wants to perform a "heart cut" of a particular portion of a sample flow corresponding, for example, to the portion representing the first peak <NUM> shown in <FIG> and described hereinabove. This "heart cut" may be stored in the storage loop <NUM>.

<FIG> depicts the system of <FIG> having the valve system switched back to the first position while receiving a flow of fluid from the second solvent delivery subsystem <NUM>, in accordance with one embodiment. In this third step of a multidimensional separation process, the "heart cut" of the particular portion of the sample stored in the storage loop <NUM> is then directed, via the second solvent delivery subsystem <NUM>, to the second dimension column path <NUM>. In particular, the solvent from the second solvent delivery subsystem <NUM> is directed by a pump system, for example, through the second valve <NUM> to the storage loop <NUM>. From the storage loop, the fluid, including the stored sample, flows back through the second valve <NUM>, which redirects the fluid back to the first valve <NUM>. From the first valve <NUM>, the fluid is then directed to the second dimension column path <NUM>, and in particular to the RPLC column <NUM>. Once the separation occurs at the RPLC column <NUM>, the fluid finally reaches the mass spectrometer <NUM> where it is detected in a second dimension. This flow of sample through each of the two column paths completes the MDLC separation process.

<FIG> depicts the system of <FIG> having the valve system <NUM> in a third position and receiving flow of fluid from the second solvent delivery system <NUM>, in accordance with one embodiment. In this embodiment, a single dimension separation and detection process of a new sample can be performed without replumbing that utilizes both the sample injection system <NUM> and the mass spectrometer <NUM> and RPLC column <NUM>. Here, the second solvent delivery subsystem <NUM> that is fluidically connected to the second valve <NUM> of the valve system <NUM> provides flow (i.e. via a pump or pump system) to the second valve <NUM> from a solvent reservoir or bottle. The flow of solvent is then directed from the second valve <NUM> to the first valve <NUM> and then the flow of solvent is directed through the sample injection system <NUM> whereby the sample is injected into the flow of solvent. The first valve <NUM> then directs the flow to the RPLC column <NUM> and the mass spectrometer <NUM>.

Switching between the valve positions in the above-described manner may be performable by an operator simply pressing a button on a user interface or other control mechanism. Thus, the system <NUM> may include a control system, processor, display or the like, for allowing an operator to control the valve system <NUM> with the switch or pressing of a button or the changing of a simple setting which redirects the valves <NUM>, <NUM> of the valve system <NUM>. Using the above-described structure, no replumbing is required when switching between an MDLC system, utilizing both the SEC column <NUM> separation and the RPLC column <NUM> and the mass spectrometer <NUM> separation, and a single dimensional separation process utilizing only the RPLC column <NUM> and the mass spectrometer <NUM>.

Thus, as described above, the valve system <NUM> is configured direct flow from the sample injection system <NUM> to the first dimension column path <NUM> and thereafter store a portion of the flow in a storage loop <NUM> (e.g. a "heart cut" portion). Moreover, the valve system <NUM> is configured to further flow the portion of the flow through the second dimension column path <NUM>. The first valve <NUM> of the valve system <NUM> is switchable from a first valve first position (e.g. shown in <FIG>) to a first valve second position (shown in <FIG>). In the first valve first position, flow is directed from the first solvent delivery subsystem <NUM> to the sample injection system <NUM>. In the first valve second position, flow is directed from the second solvent delivery subsystem <NUM> to the sample injection system <NUM>.

Moreover, in embodiments described herein, the second valve <NUM> is switchable from a second valve first position (e.g. shown in <FIG> and <FIG>) to a second valve second position (e.g. shown in <FIG> and <FIG>). In the second valve first position, flow from the first solvent delivery subsystem <NUM> is directed from the first detector <NUM> to the sample storage loop <NUM> and a path leading to the downstream waste <NUM>. In the second valve second position, fluid from the first solvent delivery subsystem <NUM> is directed from the first detector <NUM> directly to the path leading to the downstream waste <NUM> while bypassing the sample storage loop <NUM>. Moreover, in the second valve first position, flow from the second solvent delivery subsystem <NUM> is directed through the sample storage loop <NUM>, to the first valve <NUM> and to the second dimension column path <NUM>. In the second valve second position, flow from the second solvent delivery subsystem <NUM> is directed directly to the first valve <NUM> and the second dimension column path <NUM> while bypassing the sample storage loop <NUM>.

Switching can be achieved by using a valve to fluidically re-route the sample introduction from the head of the primary dimension column to the head of the second-dimension column. The first valve <NUM> is responsible for fluidically rerouting the sample introduction from the first dimension to the second dimension. The first valve <NUM> can be configured to inject onto the SEC column <NUM> or, alternatively, can inject onto the RPLC column <NUM> using the solvent flow from the second solvent delivery subsystem <NUM>.

The tubing for the system of <FIG> may be made from a range of materials including MP35N alloy, stainless steel, fused silica, and PEEK and may have inner diameters from <NUM> to <NUM>. Active preheaters (not shown) can be included in the paths leading to the two columns.

Thus, as described above, methods of dimensional selection for chromatography systems are contemplated herein. In particular, methods contemplated herein include using a valve system, such as the valve system <NUM>, of a chromatography system, such as the chromatography system <NUM>, to direct flow from a sample injection system, such as the sample injection system <NUM>, to a first dimension column path, such as the first dimension column path <NUM>, into a second dimension column path, such as the second dimension column path <NUM>, where the first dimension column path is configured to perform a first separation process in a first dimension, and where the second dimension column path is configured to perform a second separation process in a second dimension. Methods may further include switching positions of the valve system to direct flow from the sample injection system to the second dimension column path without the flow path flowing through the first dimension column path in the chromatography system.

In methods contemplated herein, a first detector, such as the first detector <NUM>, is located downstream from the first dimension column path, where the first detector is not a mass spectrometer. Similarly, in methods contemplated herein, a second detector, such as the mass spectrometer <NUM>, is located downstream from the second dimension column path, where the second detector is a mass spectrometer.

In still other embodiments, the valve system includes a first valve, such as the first valve <NUM>, fluidically connected to a first solvent delivery subsystem, such as the first solvent delivery subsystem <NUM>, and the valve system includes a second valve, such as the second valve <NUM> fluidically connected to a second solvent delivery subsystem, such as the second solvent delivery subsystem <NUM>. Methods contemplated may further include switching the first valve from a first valve first position (e.g. as shown in <FIG>) to a first valve second position (e.g. as shown in <FIG>), where in the first valve first position flow is directed from the first solvent delivery subsystem to the sample injection system, and where in the first valve second position flow is directed from the second solvent delivery subsystem to the sample injection system.

In still other embodiments, methods contemplated include switching the second valve from a second valve first position (e.g. as shown in <FIG> and <FIG>) to a second valve second position (e.g. as shown in <FIG> and <FIG>), where in the second valve first position flow from the first solvent delivery subsystem is directed from a first detector to a sample storage loop, such as the sample storage loop <NUM>, and then to a path leading to a downstream waste such as the waste pathway <NUM>, and where in the second valve second position fluid from the first solvent delivery subsystem is directed from the first detector directly to the path leading to the downstream waste while bypassing the sample storage loop.

Moreover, methods contemplated include directing flow from the second solvent delivery subsystem through the sample storage loop to the first valve and to the second dimension column path when the second valve is in the second valve first position. Methods further include directing flow from the second solvent delivery subsystem directly to the first valve and the second dimension column path while bypassing the sample storage loop when the second valve is in the second valve second position.

While embodiments of the present invention have been described herein for purposes of illustration, many modifications and changes will become apparent to those skilled in the art.

Claim 1:
A system (<NUM>) capable of performing both single and multidimensional liquid chromatography comprising:
a solvent delivery system (<NUM>);
a first dimension column path (<NUM>) configured to perform a separation process in a first dimension;
a second dimension column path (<NUM>) configured to perform a separation process in a second dimension;
a valve system (<NUM>); and
a sample injection system (<NUM>) fluidically connected to the valve system (<NUM>),
wherein the valve system (<NUM>) is configured to direct flow from the sample injection system (<NUM>) to the first dimension column path (<NUM>) when the valve system (<NUM>) is in a first position,
wherein the valve system (<NUM>) is configured to direct flow from the sample injection system (<NUM>) to the second dimension column path (<NUM>) without the flow path flowing through the first dimension column path (<NUM>) in the chromatography system (<NUM>) when the valve system (<NUM>) is in a second position, and
wherein the solvent delivery system (<NUM>) further includes:
a first solvent delivery subsystem (<NUM>) having a first pump, wherein the first solvent delivery subsystem (<NUM>) is directly fluidically connected to a first valve (<NUM>) of the valve system (<NUM>); and
a second solvent delivery subsystem (<NUM>) having a second pump, wherein the second solvent delivery subsystem (<NUM>) is directly fluidically connected to a second valve (<NUM>) of the valve system (<NUM>).