Patent Description:
The present disclosure generally relates to fluid systems used in chromatography. In particular, the present disclosure relates to systems and methods for diverting mobile phase flow within a liquid chromatography system.

Chromatography involves the flowing of a mobile phase over a stationary phase to effect separation. A detection system downstream of the separation is utilized to detect and analyze the separated sample. Chromatography systems often use a restrictor to interface to the detection system. The restrictor can be used to maintain system pressure and to regulate or introduce a portion of the mobile phase flow to the detection system.

A prior art device and method of a supercritical fluid system for detecting analytes using a low pressure detector is known from <CIT>, which uses a mobile phase output by a separation device, the mobile phase volumetrically expanding as it decompresses. The device includes a passive splitter and a shuttle valve. The passive splitter is configured to receive the mobile phase and to split the mobile phase into a primary flow stream and a split flow stream, where the primary flow stream is directed to a pressure maintenance device. The passive splitter is further configured to reduce pressure of the split flow stream, causing volumetric expansion of the split flow stream. The shuttle valve is configured to insert volumetric aliquots of the volumetrically expanded split flow stream into a dilution flow stream to provide a diluted split flow stream, and to direct the diluted split flow stream to a low pressure detector.

Diverting mobile phase flow within a liquid chromatography (LC) system raises a number of challenges, especially when dealing with fluid valves that have a larger fluidic volume and form factor than other components of the chromatography system. Technology for smoothly redirecting mobile phase flow without positioning a valve inline between the column and a detector would be beneficial and highly desirable.

According to the present invention, there is provided a method for controlling fluid flow within a liquid chromatography system as recited by Claim <NUM>. In a non-limiting example, the makeup pump is configured to pump the makeup fluid at a rate greater than the maximum flow rate of the restrictor when the fluid valve is operating in the second position. In another non-limiting example, the makeup pump is configured to pump the makeup fluid at a rate lower than the maximum flow rate of the restrictor when the valve is operating in the first position. In another non-limiting example, the detector is a mass spectrometer. In another non-limiting example, the method also includes controlling the operation of the fluid valve in order to selectively direct the output of the column to bypass the fluid valve and reach the detector at predetermined portions of a chromatographic run.

In a non-limiting example which does not form part of the present invention, operating the valve in the first position directs a majority of the output of the chromatography column to bypass the valve and reach the detector. In another non-limiting example, operating the valve in the second position directs a majority of the output of the chromatography column to waste. In another non-limiting example, the method also includes controlling the operation of the valve in order to selectively direct a majority of the output of the chromatography column to bypass the valve and reach the detector at predetermined portions of a chromatographic run. In another non-limiting example, the first pressure drop value and the second pressure drop value have a <NUM>:<NUM> ratio, and substantially <NUM>% of the output of the chromatography column bypasses the valve and is directed to the detector when the valve is operating in the first position. In another non-limiting example, the first pressure drop value and the third pressure drop value have a <NUM>:<NUM> ratio, and substantially <NUM>% of the output of the chromatography column is directed to waste via the third restrictor.

Also disclosed, but not forming part of the present invention, is a system for controlling fluid flow within a chromatography system. The system includes a mobile phase pump configured to pump a liquid mobile phase through a chromatography column. The system also includes a first restrictor positioned downstream of the chromatography column and upstream of a detector. The system also includes a valve in fluid communication with an output of the chromatography column, wherein the valve is not in a direct flow path between the chromatography column and the detector. The system also includes a computing device configured to control an operation of the valve in order to: operate the valve in a first position configured to direct the output of the chromatography column to bypass the valve and reach the detector; and operate the valve in a second position configured to direct the output of the chromatography column to waste. In a non-limiting example, the system can also include a makeup pump configured to pump a makeup fluid into the chromatography system downstream of the chromatography column and upstream of the first restrictor. In another non-limiting example, the makeup pump is configured to pump the makeup fluid at a flow rate that is less than a maximum flow rate of the first restrictor when the valve is operating in the first position. In another non-limiting example, the makeup pump is configured to pump the makeup fluid at a flow rate that is greater than a maximum flow rate of the first restrictor when the valve is operating in the second position in order to generate a backflow of the makeup fluid upstream of the first restrictor. In another non-limiting example, the valve is configured in the first position to divert a portion of output of the column to waste through a second restrictor having a pressure drop value much greater than the first restrictor. In another non-limiting example, the valve is configured in the second position to divert a portion of output of the column to waste through a third restrictor having a pressure drop value much less than the first restrictor.

Also disclosed, but not forming part of the present invention, is a system for controlling fluid flow within a chromatography system. The system includes a mobile phase pump configured to pump a liquid mobile phase through a chromatography column. The system also includes a first restrictor positioned downstream of the chromatography column and upstream of a detector. The system also includes a valve in fluid communication with an output of the chromatography column, wherein the valve is not in a direct flow path between the chromatography column and the detector, the valve configured to operate in a first position configured to direct the output of the chromatography column to bypass the valve and reach the detector or to operate in a second position configured to direct the output of the chromatography column to waste. In a non-limiting example, the system can also include a makeup pump configured to pump a makeup fluid into the chromatography system downstream of the chromatography column and upstream of the first restrictor; wherein the makeup pump is configured to pump the makeup fluid at a flow rate that is less than a maximum flow rate of the first restrictor when the valve is operating in the first position, and is configured to pump the makeup fluid at a flow rate that is greater than a maximum flow rate of the first restrictor when the valve is operating in the second position in order to generate a backflow of the makeup fluid upstream of the first restrictor. In another non-limiting example, the system can include a second restrictor having a pressure drop value much greater than the first restrictor, and a third restrictor having a pressure drop value much less than the first restrictor; wherein the fluid valve is configured in the first position to divert a portion of the output of the chromatography column to waste through the second restrictor, and in the second position to divert a portion of the output of the chromatography column to waste through the third restrictor.

The above aspects of the technology provide numerous advantages. For example, systems and methods of the present technology allow for flow splitting without the need for a valve directly in the flow line to the detector. Examples of the present technology also allow flow diversion to be implemented with lower post-column volume than previous techniques. The present technology can also reduce post-column system dispersion because the valve is no longer positioned within the analytical elution path.

One of ordinary skill in the art will understand that the drawings primarily are for illustrative purposes and are not intended to limit the scope of the inventive subject matter described herein. The drawings are not necessarily to scale; in some instances, various aspects of the subject matter disclosed herein may be shown exaggerated or enlarged in the drawings to facilitate an understanding of different features. In the drawings, like reference characters generally refer to like features (e.g., functionally similar and/or structurally similar elements).

The features and advantages of the present disclosure will become more apparent from the detailed description set forth below when taken in conjunction with the drawings.

Following below are more detailed descriptions of various concepts related to, and embodiments of, methodologies, apparatus and systems for controlling fluid flow within a chromatography system. It should be appreciated that various concepts introduced above and discussed in greater detail below may be implemented in any of numerous ways, as the disclosed concepts are not limited to any particular manner of implementation. Examples of specific implementations and applications are provided primarily for illustrative purposes.

As used herein, the term "includes" means includes but is not limited to, the term "including" means including but not limited to.

A "restrictor" herein refers to a component used in a chromatography system that is used to regulate or decrease flow. In some embodiments a restrictor is also used to interface to a detection component. Non-limiting examples of restrictors include a length of straight, small internal diameter tubing, a tapered restrictor, a converging-diverging restrictor, an integral restrictor, or a fritted restrictor. Non-limiting examples of active restrictors include a variable restrictor, a thermally modulated variable restrictor, or a back pressure regulator.

When coupling chromatography to mass spectrometry (MS), flow diversion is often employed. In some cases, flow diversion only introduces the portion of the chromatographic mobile phase which contains analytes of interest. During other portions of the chromatographic elution, the mobile phase is diverted away from the detector in order to keep the detector as clean as possible longer. In some cases, a simple valve can be employed to direct the flow to and away from the detector. Flow diversion can be used in a coupled LC-MS system to reduce contamination of the MS hardware and to increase the robustness and uptime. In some embodiments, a diverter valve, such as a rotary shear valve, can be plumbed in-line downstream of the chromatography column in order to direct flow into, or away from, the MS inlet. Flow diversion can often be employed in high-throughput applications with 'dirty' sample matrices. The column effluent is typically diverted to waste during the first and last portions of a separation. Highly polar compounds, such as salts, elute at the beginning of a reversed-phase LC separation, being substantially unretained. The last portion of a separation is often a wash step which cleans the column of highly nonpolar compounds. In either case, these compound groups have little analytical value and can cause needless contamination of the MS components, such as sampling cones, ion optics, and other inlet components. In cases where severe contamination of MS components has occurred, performance can be significantly compromised, and can ultimately result in complete loss of mass spectrometer signal. A complete tear-down and cleaning of the system may be required to restore normal operation. Such a tear-down implies multiple hours to days of system down-time. Accordingly, it is in the best interest of the analyst to keep the mass spectrometer components as clean as possible, for as long as possible.

<FIG> illustrate an example block diagram of a prior art chromatography system <NUM> that utilizes a valve <NUM>, such as a rotary shear valve, to direct the output of a chromatography column <NUM> either to waste <NUM> or to a detector <NUM>. The system may include a mobile phase pump or sample introduction component <NUM> connected to the column <NUM>. During a chromatographic run, the output of the column <NUM> is often of least interest at the beginning and/or end of the run. In some cases, the valve <NUM> can direct the output of the column to waste <NUM> during those time periods of least interest. The valve <NUM> can include, for example, a simple rotary shear valve. In a non-limiting example, the detector <NUM> can include a mass spectrometer.

<FIG> shows an example embodiment where the system <NUM> is in a non-divert or flow-through state where the output of the chromatography column <NUM> is directed through the valve <NUM> and to the detector <NUM>. <FIG> shows an example embodiment where the system <NUM> is in a diverting state where the output of the chromatography column <NUM> is directed to waste <NUM>. Such a system can be simple to implement and automate. However, such a system can include additional post-column volume introduced by the fluidics of the divert valve <NUM>. Furthermore, the bulk or large external size of the valve <NUM> is interposed within the space-constrained region between the output of the column <NUM> and the inlet of the detector <NUM> or mass spectrometer. Furthermore, the detector <NUM> or spectrometer ion source is running dry (i.e. with zero fluid flow) during the divert operation. The additional post-column fluidic volume of the valve <NUM> can promote chromatographic band-broadening, thus reducing separation performance. The bulk or large external size of the valve <NUM> hinders or prevents the implementation of this configuration in space-constrained regions within integrated LC-MS systems. In addition, running a MS ion source inlet dry can cause plugging due to sample/matrix precipitation and/or overheating of ion source components.

<FIG> is a graph <NUM> showing a trace <NUM> of the MS response to a continuously-infused caffeine sample introduced at <NUM>, <NUM>, and <NUM>µL/min within the system of <FIG>. In this particular example, the system <NUM> described above in reference to <FIG> is toggled at each flow rate between the operating or flow-through state described in reference to <FIG>, and the divert state described in reference to <FIG>. As shown in <FIG>, the drop of signal during the divert state at each flow rate shows excellent performance of the divert system. The reduction of signal is proportional to the amount of sample directed away from the MS. In this case, absence of response implies a <NUM>%-effective divert system.

As discussed above, however, this approach can consume significant space within one of the most space-constrained regions of a chromatography system. Implementing the divert valve in-line can also impart an undesired amount of post-column fluidic volume arising from the valve hardware, the intervening tubing, and the multiple fluidic connections. According to embodiments of the present invention, a low-volume solid-state post column diversion system is disclosed which can be implemented within significantly smaller spaces.

<FIG> show a block diagram of a novel flow-divert system <NUM> employing a makeup pump <NUM> and a restrictor <NUM>, according to an embodiment of the present disclosure. In this particular embodiment, the system <NUM> includes a mobile phase pump or sample introduction component <NUM>, a chromatography column <NUM>, a restrictor <NUM> positioned upstream of a detector <NUM> or MS, a set of low volume tees <NUM>, <NUM> such as nano-tees (i.e. fluid tees that are configured to direct fluid at the nL scale) positioned upstream of the restrictor <NUM> and in fluid communication with ports in a valve <NUM>. The makeup pump <NUM> is in fluid communication with the valve <NUM> such that the output of the makeup pump <NUM> can be selectively directed through the valve <NUM> to the input of the second nano-tee <NUM> or to the input of the first nano-tee <NUM> via a third tee <NUM>. In a non-limiting example, the makeup pump <NUM> is configured to pump a makeup fluid having the same composition as a mobile phase solvent exiting the column <NUM>. When the system <NUM> is in an operating state, as shown in <FIG>, the waste <NUM> is connected with a plug <NUM> and the output of the column <NUM> is directed to the detector <NUM>. However, when the system <NUM> is in a divert state, as shown in <FIG>, the output of the column <NUM> is directed to waste <NUM> through the third tee <NUM> and the valve <NUM>.

In a non-limiting example, the makeup pump <NUM>, valve <NUM>, and third tee <NUM> hardware lie along a non-critical flow path to waste <NUM>, rather than in-line between the chromatography column <NUM> and the detector <NUM>. This non-critical flow path is shown in region <NUM>, rather than in region <NUM> between the column <NUM> and the detector <NUM>. Thus, each of these components can be positioned in locations-of-convenience anywhere in reasonable proximity to the detector <NUM> or MS. In this way, these components do not need to occupy highly-critical space directly between the column <NUM> outlet and the detector <NUM> inlet, as bandspread within these lines is not a performance consideration.

In the operating state shown in <FIG>, the column <NUM> effluent is directed through the restrictor <NUM> to the MS detector <NUM>. The makeup pump <NUM> can operate at a very low flow rate to flush the two side lines and prevent analyte diffusion into the side lines located between the nano-tees <NUM>, <NUM> and the valve <NUM> (with concomitant band-broadening and/or sample-carryover effect).

In the divert state shown in <FIG>, the column <NUM> flow is directed to waste <NUM> due to the backflow created by directing the output of the makeup pump <NUM> upstream of the restrictor <NUM> at a flow rate that is higher than the maximum flow rate of the restrictor <NUM>. In this way, only makeup fluid is introduced to the MS and all column effluent is directed to waste <NUM>. The restrictor <NUM> can be designed to minimize the makeup fluid flow required to effect diversion, while not contributing a large parasitic pressure demand upon the LC system. In another non-limiting example, an optional restrictor could be added to the waste path to prevent all of the combined mobile phase and makeup fluid from flowing to waste. This optional restrictor could be designed to form a restriction bridge with the first restrictor in order to balance the flow and direct some to waste and some to the detector <NUM>. The makeup fluid could still be high enough, in some embodiments, that all mobile phase is directed to waste and only makeup fluid is directed to the detector <NUM>.

<FIG> is a graph <NUM> showing a trace <NUM> of the MS response to a continuously-infused caffeine sample introduced at <NUM>, <NUM>, and <NUM>µL/min within the system of <FIG>. In this particular example, the system <NUM> described above in reference to <FIG> is toggled at each flow rate between the operating or flow-through state described in reference to <FIG>, and the divert state described in reference to <FIG>. As shown in <FIG>, the drop of signal during the divert state at each flow rate shows excellent performance of the divert system.

<FIG> show a block diagram of a novel flow-divert system <NUM> employing restrictors <NUM>, <NUM>, <NUM> in a flow splitting arrangement, according to an embodiment of the present disclosure. In a non-limiting example, the system includes a mobile phase pump or sample introduction component <NUM>, a chromatography column <NUM>, a small volume tee <NUM> such as a nano-tee, a first restrictor <NUM> positioned upstream of a detector <NUM>, and a valve <NUM> in fluid communication with the nano-tee <NUM>. The waste <NUM> is in fluid communication with a second tee <NUM> that is connected to the valve <NUM> via a second restrictor <NUM> and a third restrictor <NUM>. In this example embodiment, the second restrictor <NUM> has a pressure drop much greater than the first restrictor <NUM>, while the third restrictor <NUM> has a pressure drop much less than the first restrictor <NUM>.

In a non-limiting example, the restrictors <NUM>, <NUM>, <NUM> are designed to establish a <NUM>:<NUM> split ratio between the MS detector <NUM> and waste <NUM>. For example, the first restrictor <NUM> can be configured with a pressure drop of approximately <NUM> kPa/mL/min (<NUM> PSI/mL/min) (approximately <NUM> bar/mL/min), the second restrictor <NUM> with a pressure drop of approximately <NUM> kPa/mL/min (<NUM> PSI/mL/min) (approximately <NUM>,<NUM> bar/mL/min), and the third restrictor <NUM> with a pressure drop of approximately <NUM> kPa/mL/min (<NUM> PSI/mL/min) (approximately <NUM> bar/mL/min). According to one example embodiment, the operating state shown in <FIG> creates a <NUM>:<NUM> split ratio between the second restrictor <NUM> and the first restrictor <NUM>, thus directing <NUM>% of the output of the column <NUM> to the detector <NUM> via the first restrictor <NUM>. In this example embodiment, <NUM>% of the output of the column is intentionally directed to waste during normal operation in order to prevent analyte diffusion into and out of the side channel (i.e. to prevent peak tailing). In another non-limiting example, the divert state shown in <FIG> creates a <NUM>:<NUM> split ratio between the first restrictor <NUM> and the third restrictor <NUM>, thus directing <NUM>% of the output of the column <NUM> to waste <NUM> via the third restrictor <NUM>. In a non-limiting example, the first restrictor <NUM> can have dimensions of approximately <NUM> x <NUM>, the second restrictor <NUM> can have dimensions of approximately <NUM> x <NUM>, and the third restrictor <NUM> can have dimensions of approximately <NUM> x <NUM>. In an alternative embodiment, the waste lines can be two independent lines from the second and third restrictors <NUM>, <NUM> rather than being tee'd together, as shown in <FIG>.

<FIG> is a graph <NUM> showing a trace <NUM> of the MS response to a continuously-infused caffeine sample introduced at <NUM>, <NUM>, and <NUM>µL/min within the system of <FIG>. In this particular example, the system <NUM> described above in reference to <FIG> is toggled at each flow rate between the operating or flow-through state described in reference to <FIG>, and the divert state described in reference to <FIG>. As shown in <FIG>, the drop of signal during the divert state at each flow rate shows excellent performance of the divert system. Some example advantages to this invention include reduced post column system dispersion and the ability to implement a divert functionality within a very limited post-column space such as when a vacuum-jacketed column is placed inside an MS probe, or within a fully integrated LC-MS system, or on a microfluidic separation platform.

Flow-modulated diversion, such as described above in reference to <FIG>, can provide a number of advantages such as: (<NUM>) low post-column volume, (<NUM>) ability to be implemented in systems which are extremely space-constrained just upstream of the ion source (e.g. where a vacuum-jacketed column is located within an MS probe, fully integrated LC-MS systems, or on a microfluidic separation platform), and (<NUM>) the spectrometer ion source is always maintained "wet," or with liquid flow. Reduced post column system dispersion can also be accomplished due to the fact that valves are no longer present within the analytical elution path (i.e. in-line with the analytical flow).

<FIG> is a flowchart illustrating an exemplary method <NUM> for controlling fluid flow within a chromatography system, according to an embodiment of the present disclosure. It will be appreciated that the method can be programmatically performed, at least in part, by one or more computer-executable processes executing on, or in communication with, one or more servers or other computing devices such as those described further below. In step <NUM>, the chromatography process is initiated by activating the mobile phase pump. In some example embodiments, the chromatography system is a liquid chromatography system, and the mobile phase pump is configured to pump a mobile phase through a chromatography column.

In step <NUM>, a makeup pump is activated. In a non-limiting example, the makeup pump can be implemented as shown in <FIG> and can be in fluid communication with a valve, such as a rotary shear valve. When activated, the makeup pump can pump a makeup fluid to the fluid valve that is in fluid communication with the output of the chromatography column and a channel to waste. The makeup pump can be configured to pump the makeup fluid at various flow rates, and the flow rate of the makeup pump can be controlled, in some embodiments, by a computing device or pump controller.

In step <NUM>, the maximum flow rate of a restrictor positioned upstream of a detector and downstream of the chromatography column is determined. The detector is also positioned downstream of the fluid valve, as shown in the example embodiments of <FIG>. The detector can be, for example, a mass spectrometer or a flame ionization detector.

In step <NUM>, it is determined whether the mobile phase exiting the chromatography column should be directed to the detector. As discussed above, the output of the column may sometimes be selectively directed to waste at the beginning and end of a chromatographic run, and only directed to the detector at specific times. If it is determined that the output of the chromatography column should be directed to the detector, the method continues in step <NUM> by operating the valve in the first position configured to divert the makeup fluid through the fluid valve to join the output of the chromatography column. The makeup pump can be directed through the valve and into a first tee <NUM>, as shown in <FIG>, and introduced to the output of the chromatography column using a low-volume tee <NUM> such as a nano-tee. In a non-limiting example, the makeup pump is configured to pump the makeup fluid at a flow rate well below the maximum flow rate of the restrictor when the valve is operating in the first position. This allows the makeup fluid to maintain a small fluid flow within the lines connecting the valve <NUM> with the low-volume tees <NUM>, <NUM> as discussed above.

If it is determined that the output of the chromatography column should be directed to waste, the method continues with step <NUM> and the valve operates in a second position configured to direct the makeup fluid through the fluid valve directly upstream of the restrictor in order to create a backflow at the restrictor and divert the output of the chromatography column to waste via the valve. An example of this second valve position can be seen in <FIG>, where the makeup fluid from the makeup pump <NUM> is introduced directly upstream of the restrictor <NUM> via a low-volume tee <NUM> in order to create a backflow of makeup fluid upstream of the restrictor <NUM>. In a non-limiting example, the makeup pump is configured to pump the makeup fluid at a rate greater than the maximum flow rate of the restrictor while the valve is operating in the second position. According to an example embodiment, the method described above allows a user to control the operation of the fluid valve in order to selectively direct the output of the chromatography column to bypass the valve and reach the detector at predetermined portions of a chromatographic run. As will be appreciated, the operation of the fluid valve can be controlled, in some embodiments, using a programmable computer or processing device.

<FIG> is a flowchart illustrating another exemplary method <NUM> for controlling fluid flow within a chromatography system, according to an embodiment of the present disclosure. It will be appreciated that the method can be programmatically performed, at least in part, by one or more computer-executable processes executing on, or in communication with, one or more servers or other computing devices such as those described further below. In step <NUM>, the chromatography process is initiated by activating the mobile phase pump. In some example embodiments, the chromatography system is a liquid chromatography system, and the mobile phase pump is configured to pump a mobile phase through a chromatography column.

In step <NUM>, a portion of the output of the column is diverted to a valve. In a non-limiting example, the portion of the output of the column can be diverted using a low-volume tee and the valve can be implemented as shown in <FIG>. As shown in this non-limiting example, the tee <NUM> can be positioned directly upstream of a first restrictor, and the valve can selectively direct the diverted portion of the output of the column to waste via either a second restrictor or a third restrictor. In a non-limiting example, the pressure drop value across the first restrictor is much lower than the pressure drop value across the second restrictor, and the pressure drop value across the first restrictor is much higher than the pressure drop value across the third restrictor.

In step <NUM>, it is determined whether the mobile phase exiting the chromatography column should be directed to the detector. As discussed above, the output of the column may sometimes be selectively directed to waste at the beginning and end of a chromatographic run, and only directed to the detector at specific times. If it is determined that the output of the chromatography column should be directed to the detector, the method continues in step <NUM> by operating the valve in the first position configured to direct the diverted portion of the output of the chromatography column to waste through the second restrictor. A non-limiting example of the valve operating in the first position is shown in <FIG>, where the portion of the output of the chromatography column diverted at tee <NUM> away from the first restrictor <NUM> is directed to waste <NUM> through the valve <NUM> and the second restrictor <NUM>. In this particular example, because the pressure drop value across the second restrictor <NUM> is larger than the pressure drop value across the first restrictor <NUM>, a majority of the output of the chromatography column is directed to the detector <NUM> through the first restrictor <NUM>. In another non-limiting example, the first pressure drop value associated with the first restrictor and the second pressure drop value associated with the second restrictor have a ratio of <NUM>:<NUM> such that substantially <NUM>% of the output of the chromatography column is directed to the detector when the valve is operating in the first position.

If it is determined that the output of the chromatography column should be directed to waste, the method continues in step <NUM> by operating the valve in the second position configured to direct the diverted portion of the output of the chromatography column to waste through the third restrictor. A non-limiting example of the valve operating in the second position is shown in <FIG>, where the portion of the output of the chromatography column diverted at tee <NUM> away from the first restrictor <NUM> is directed to waste <NUM> through the valve <NUM> and the third restrictor <NUM>. In this particular example, because the pressure drop value across the third restrictor <NUM> is less than the pressure drop value across the first restrictor <NUM>, a majority of the output of the chromatography column is directed to waste <NUM> through the third restrictor <NUM>. In another non-limiting example, the first pressure drop value associated with the first restrictor and the third pressure drop value associated with the third restrictor have a ratio of <NUM>:<NUM> such that substantially <NUM>% of the output of the chromatography column is directed to waste when the valve is operating in the second position.

<FIG> shows a non-limiting example apparatus <NUM> that can be used to implement an example method for controlling fluid flow within a chromatography system, according to the principles described herein. The apparatus <NUM> can include at least one memory <NUM> and at least one processing unit <NUM>. The processing unit <NUM> can be communicatively coupled to the at least one memory <NUM> and also to at least one component of a chromatography system <NUM>, such as the valve, mobile phase pump, makeup pump, or other components described herein.

Claim 1:
A method for controlling fluid flow within a liquid chromatography system, said system comprising a fluid valve (<NUM>) in fluid communication with a makeup pump (<NUM>), an output of a chromatography column (<NUM>), and a channel to waste (<NUM>), said method comprising:
operating said fluid valve (<NUM>) in a first position configured to divert said makeup fluid through the fluid valve to join the output of the chromatography column and configured to direct the output of the chromatography column to bypass the fluid valve and flow through a restrictor (<NUM>) and to a detector (<NUM>), wherein the restrictor is located downstream of the column, downstream of the fluid valve, and upstream of the detector;
operating the fluid valve in a second position configured to divert the makeup fluid through the fluid valve directly upstream of the restrictor and configured to create
a backflow of the makeup fluid at the restrictor to divert the output of the chromatography column to waste (<NUM>) via the fluid valve.