Methods and systems for reducing column bleed carryover effects

Abstract

In gas chromatography (GC), a sample is introduced into a carrier gas stream and the mixture is driven through a heated GC column to obtain chromatographic data from the sample. During this time, the column is heated from an initial temperature to a final temperature. Subsequently, the column is cooled according to a cooling program. The cooling program may include a first cooling ramp, a subsequent isothermal hold, and a subsequent second cooling ramp. Optionally, when the column is cooling, the carrier gas flow through the column can be slowed or stopped for a period of time, after which the carrier gas flow through the column can be restored to the original flow rate to prepare for processing another sample. Controlling the column temperature and / or flow rate in this way can be effective in reducing column bleed carryover and / or its effects.

Description

[0001] This divisional application of the present invention is based on a patent application with an application date of June 29, 2016, an application number of 2016800873043, and an invention title of "Methods and Systems for Reducing Column Bleed Carryover Effect". Technical Field

[0002] The present invention generally relates to gas chromatography (GC), and more particularly to controlling column temperature and flow rate during the GC column cooling time such that the column bleed carryover effect can be reduced. Background of the Invention

[0003] Gas chromatography (GC) necessarily requires the analytical separation of vaporized or gaseous samples injected into a chromatographic column. A chemically inert carrier gas (such as helium, nitrogen, argon, or hydrogen) is used as the mobile phase for eluting the analyte sample in the column. The sample and the carrier gas are introduced into a GC inlet coupled to the head of the column. In this GC inlet, the sample is injected into the carrier gas stream, and the resulting sample-carrier gas mixture is passed through the column. This is referred to as column flow. During column flow, the sample encounters a stationary phase (typically a material lining the inner surface of the column), which causes the different components of the sample to separate according to their different affinities for the stationary phase. These separated components elute from the column outlet and are measured by an appropriate detector, generating data from which a chromatogram or spectrum identifying the components can be constructed. When the sample flows through the column, the column (and thus the sample) is maintained at a desired temperature. For this purpose, the column is typically housed in a temperature-controlled oven or positioned in thermal contact with a heating device. Temperature programming of the column allows for the analysis of a wider range of components in a single run. If a temperature program is used, the column is typically cooled to the method start temperature between sample runs.

[0004] Changing the column temperature also affects the stationary phase. Typically, the stationary phase is stable at the initial column temperature and does not change even after long periods under these conditions. However, as the temperature increases, the stationary phase may start to degrade. When it degrades, decomposition products are produced, and these decomposition products are volatile enough that at higher temperatures they are not retained by the stationary phase or are partially retained by the stationary phase and generate a signal for some types of detectors. This signal is added to the signal generated by the elution of the components of the analyzed sample, increasing the baseline signal level. This is referred to as column bleed, and most of the time it is easily distinguishable from the peaks generated by the elution of the components of the analyzed sample.

[0005] As noted, column bleed typically is not retained at the highest temperatures and is typically completely retained at the lowest temperatures, i.e., the decomposition products are retained in fixed positions within the column. At intermediate temperatures, the column bleed is partially retained. When a new sample run begins and the column temperature begins to ramp up, if there is still some column bleed from a previous sample run present in the column, it will begin to elute out, causing the baseline to rise. Eventually, this will combine with newly formed column bleed and the baseline will rise further. Additionally, the effects of this are typically small because column bleed typically produces a broad signal that does not confuse with peaks.

[0006] However, there is a situation in which column bleed can become a more serious problem. If the retained column bleed from a previous run begins to elute out and it is not evenly distributed within the column, then it can produce what looks like peaks in the chromatogram and this can interfere with the analysis of the sample. If the column cools very rapidly after a previous run, and especially if the column is not cooled evenly, the retained column bleed can become unevenly distributed within the column. Since the carrier gas is still flowing during the cooling process, the column bleed components will tend to migrate from the hotter parts of the column to the cooler parts. The longer the column spends in this intermediate temperature region and the more uneven the column temperature is during this time, the greater the separation of the column bleed between the parts of the column.

[0007] When the column temperature rises at the start of the next run, if the temperature rises slowly enough, then the residual column bleed bags elute out as fairly broad peaks that are easily distinguishable from the much sharper peaks of the analyzed sample. The faster the temperature rises, the narrower these column bleed peaks become until they start to cause problems. One can minimize this effect by cooling the column slowly and evenly or by heating the column more gradually at the start of a sample run, but either of these strategies will increase the time between sample runs and reduce the sample throughput.

[0008] There is still a need for methods and systems for reducing the column bleed effect caused by the thermal induced decomposition of the stationary phase in a GC column. SUMMARY OF THE INVENTION

[0009] To address the foregoing problems (in whole or in part) and / or other problems that the skilled person in the art may have observed, the present disclosure provides methods, processes, systems, devices, instruments, and / or equipment as described in the implementations listed below by way of example.

[0010] According to one embodiment, a method for performing gas chromatography (GC) on a sample includes: flowing a carrier gas through a GC column; during a sample run time, heating the GC column according to a heating program that includes increasing the column temperature of the GC column from an initial column temperature to a final column temperature; during the sample run time, injecting the sample into the flowing carrier gas to produce a mixture of the sample and the carrier gas and flowing the mixture through the GC column; and after the sample run time, cooling the GC column according to a cooling program that includes: reducing the column temperature from the final column temperature to a hold temperature; maintaining the column temperature at the hold temperature for an isothermal hold time; and after the isothermal hold time, reducing the column temperature from the hold temperature to the initial column temperature. Optionally, during the isothermal hold time, the flow of the carrier gas through the column can be increased to and maintained at a hold flow rate or a hold pressure.

[0011] According to another embodiment, a gas chromatography (GC) system includes: a GC column; a carrier gas source configured to flow a mixture of a sample and a carrier gas through the GC column; a heating device configured to heat the GC column; and a controller configured to: control the carrier gas source to flow the mixture through the GC column during a sample run time; control the heating device to heat the GC column according to a heating program during the sample run time, the heating program including increasing the column temperature of the GC column from an initial column temperature to a final column temperature; and control the heating device to cool the GC column according to a cooling program after the sample run time, the cooling program including: reducing the column temperature from the final column temperature to a hold temperature; maintaining the column temperature at the hold temperature for an isothermal hold time; and after the isothermal hold time, reducing the column temperature from the hold temperature to the initial column temperature. Optionally, during the isothermal hold time, the flow rate of the carrier gas through the column can be increased to and maintained at a hold flow rate or a hold pressure.

[0012] According to another embodiment, a method for performing gas chromatography (GC) on a sample includes: flowing a carrier gas through a GC column; during a sample run, heating the GC column to a predetermined temperature or heating the GC column according to a predetermined temperature profile; during the sample run time, injecting the sample into the flowing carrier gas to produce a mixture of the sample and the carrier gas and flowing the mixture through the GC column; after the sample run time, cooling the GC column during a cooling time; and reducing or terminating the flow of the carrier gas through the GC column before and / or during at least an initial portion of the cooling time.

[0013] According to another embodiment, a gas chromatography (GC) system includes: a GC column; a carrier gas source configured to flow a mixture of a sample and a carrier gas through the GC column; a heating device configured to heat the GC column; and a controller configured to: control the carrier gas source to flow the mixture through the GC column and to a detector; control the heating device to heat the GC column to a predetermined temperature or heat the GC column according to a predetermined temperature profile during a sample run; control the cooling of the GC column during a cooling period after the sample run time; and control the carrier gas source or a flow regulator between the carrier gas source and the GC column to reduce or stop the flow of the carrier gas through the GC column before and / or during at least an initial portion of the cooling period.

[0014] According to another embodiment, a method for performing gas chromatography (GC) on a sample includes: flowing a carrier gas through a GC column; heating the GC column to a predetermined temperature or heating the GC column according to a predetermined temperature profile during a sample run; injecting the sample into the flowing carrier gas to produce a mixture of the sample and the carrier gas; flowing the mixture through the GC column; after analysis is complete, cooling the GC column during a cooling period; and during at least a portion of the cooling period, slowing the flow of the carrier gas through the GC column to a rate less than the flow rate of the carrier gas through the column during the analysis.

[0015] According to another embodiment, a gas chromatography (GC) system or apparatus includes: a GC column having a column inlet and a column outlet; a carrier gas source configured to flow a mixture of a sample and a carrier gas into the column inlet; a detector configured to detect an analyte of the mixture flowing out of the column outlet; a heating device configured to heat the GC column; and a controller configured to: control the carrier gas source to flow the carrier gas and the sample through the GC column and to the detector; control the heating device to heat the GC column to a predetermined temperature or heat the GC column according to a predetermined temperature profile during a sample run; control the cooling of the GC column; and control the carrier gas source to slow the flow of the carrier gas through the GC column to a rate less than the flow rate of the carrier gas through the column during the sample run time during at least a period of the cooling period.

[0016] According to another embodiment, a gas chromatography (GC) system or apparatus is configured to perform or control any of the methods disclosed herein.

[0017] After examining the following drawings and detailed description, other devices, apparatuses, systems, methods, features, and advantages of the present invention will be clear or will become clear to those skilled in the art. It is intended that all such additional systems, methods, features, and advantages be included in this specification, within the scope of the present invention, and be protected by the appended claims.

[0018] The present invention includes:

[0019] 1. A method for performing gas chromatography (GC) on a sample, the method comprising:

[0020] Passing a carrier gas through a GC column;

[0021] During a sample run time, heating the GC column according to a heating program, the heating program including raising the column temperature of the GC column from an initial temperature to a final temperature;

[0022] During the sample run time, injecting the sample into the flowing carrier gas to produce a mixture of the sample and the carrier gas, and passing the mixture through the GC column; and

[0023] After the sample run time, cooling the GC column according to a cooling program, the cooling program including:

[0024] Lowering the column temperature from the final temperature to a hold temperature;

[0025] Maintaining the column temperature at the hold temperature for an isothermal hold time; and

[0026] After the isothermal hold time, lowering the column temperature from the hold temperature to the initial temperature.

[0027] 2. The method according to item 1, wherein the hold temperature is a temperature that is cold enough to substantially avoid decomposition of the stationary phase of the GC column phase and warm enough to facilitate flushing out decomposition products present in the GC column before the sample run time.

[0028] 3. The method according to item 1, wherein the hold temperature is in the range of from about 20 °C to about 100 °C lower than the final temperature.

[0029] 4. The method according to item 1, wherein the isothermal hold time is a period of time that effectively allows decomposition products present in the GC column before the sample run time to be flushed out of the GC column.

[0030] 5. The method according to item 1, which includes defining a flush time as the sum of the duration of the column temperature decreasing from the final temperature to the hold temperature and the isothermal hold time, wherein the flush time is selected from the group consisting of: a period of time in the range of from about 1 times to about 4 times the void time of the GC column; and a period of time in the range of from about 1 minute to 5 minutes.

[0031] 6. The method according to item 1, wherein the column temperature is reduced from the final temperature to the hold temperature, or the column temperature is reduced from the hold temperature to the initial temperature, or both of the foregoing, at a cooling rate in the range from 100 °C / min to 1000 °C / min.

[0032] 7. The method according to item 1, wherein the column temperature is reduced from the final temperature to the hold temperature at a first cooling rate, the column temperature is reduced from the hold temperature to the initial temperature at a second cooling rate, and the first cooling rate is greater than the second cooling rate.

[0033] 8. The method according to item 1, which includes increasing the column flow rate from an initial flow rate to an elevated flow rate at or after the start time of the isothermal hold time while maintaining the column temperature at the hold temperature, and maintaining the column flow rate at the elevated flow rate for a flow rate hold time that spans at least a portion of the isothermal hold time.

[0034] 9. The method according to item 8, wherein increasing the column flow rate includes increasing the column inlet pressure.

[0035] 10. The method according to item 1, which includes flowing the mixture from the GC column to a detector during the sample run time to obtain chromatographic data from the sample.

[0036] 11. The method according to item 1, wherein cooling the GC column according to the cooling program is performed after the analyte of interest has been eluted from the column.

[0037] 12. A gas chromatography (GC) system, comprising:

[0038] A GC column;

[0039] A carrier gas source configured to flow a mixture of a sample and a carrier gas through the GC column;

[0040] A heating device configured to heat the GC column; and

[0041] A controller configured to:

[0042] Control the carrier gas source to flow the mixture through the GC column during the sample run time;

[0043] Control the heating device to heat the GC column according to a heating program during the sample run time, the heating program including increasing the column temperature of the GC column from an initial temperature to a final temperature; and

[0044] Control the heating device to cool the GC column according to a cooling program after the sample run time, the cooling program including:

[0045] Reduce the column temperature from this final temperature to the hold temperature;

[0046] Maintain the column temperature at this hold temperature for an isothermal hold time; and

[0047] After this isothermal hold time, reduce the column temperature from this hold temperature to the initial temperature.

[0048] 13. The GC system according to item 12, wherein the controller is configured to maintain the hold temperature within a range of from about 20 °C to about 100 °C below the final temperature.

[0049] 14. The GC system according to item 12, wherein the flush time is defined as the sum of the duration of the reduction of the column temperature from the final temperature to the hold temperature and the isothermal hold time, and wherein the controller is configured to control the heating device such that the flush time is selected from the group consisting of: a time period within a range of from about 1 times to about 4 times the void time of the GC column; and a time period within a range of from about 1 minute to 5 minutes.

[0050] 15. The GC system according to item 12, wherein the controller is configured to control the heating device such that the reduction of the column temperature from the final temperature to the hold temperature, or the reduction of the column temperature from the hold temperature to the initial temperature, or both of the foregoing, occurs at a cooling rate within a range of from 100 °C / min to 1000 °C / min.

[0051] 16. The GC system according to item 12, wherein the controller is configured to control the heating device such that the reduction of the column temperature from the final temperature to the hold temperature occurs at a first cooling rate, the reduction of the column temperature from the hold temperature to the initial temperature occurs at a second cooling rate, and the first cooling rate is greater than the second cooling rate.

[0052] 17. The GC system according to item 12, wherein the controller is configured to:

[0053] At or after the start time of maintaining the column temperature at this hold temperature for the isothermal hold time, increase the column flow rate from the initial flow rate to an elevated flow rate and maintain the flow rate at this elevated flow rate for a flow rate hold time that spans at least a portion of the isothermal hold time.

[0054] 18. The GC system according to item 12, which includes a cooling device configured to actively cool the GC column, wherein the controller is configured to control the cooling device to cool the GC column according to the cooling program after the sample run time.

[0055] 19. A method for performing gas chromatography (GC) on a sample, the method comprising:

[0056] Passing a carrier gas through a GC column;

[0057] During a sample run time, heating the GC column to a predetermined temperature or heating the GC column according to a predetermined temperature profile;

[0058] During the sample run time, injecting the sample into the flowing carrier gas to produce a mixture of the sample and the carrier gas, and passing the mixture through the GC column;

[0059] After the sample run time, cooling the GC column during a cooling time; and

[0060] During at least an initial portion of the cooling time, reducing or terminating the flow of the carrier gas through the GC column.

[0061] 20. A non-transitory computer-readable medium having instructions stored thereon that, when executed by a processor, control or perform the cooling of a GC column according to the method of item 1. Brief Description of the Drawings

[0062] The present invention can be better understood by reference to the following drawings. Components in the drawings are not necessarily to scale, but rather the emphasis is placed on illustrating the principles of the invention. In the drawings, the same reference numerals refer to corresponding components in all these different views.

[0063] Figure 1 is a schematic diagram of an example of a gas chromatography (GC) system or apparatus according to a representative embodiment.

[0064] Figure 2 is a schematic diagram of a GC column and associated components according to an embodiment.

[0065] Figure 3 shows an example of a column temperature program (or profile) implemented in a GC system according to an embodiment.

[0066] Figure 4 is a flow chart showing an example of a method for performing gas chromatography (GC) on a sample according to an embodiment.

[0067] Figure 5 is a set of three chromatograms obtained from three consecutive sample runs using a GC system as described herein.

[0068] Figure 6 is a graph of ASTM noise versus residence temperature for four different residence times generated by an experiment as described herein.

[0069] Figure 7 It is a graph showing the variation of a set of ASTM noise with the number of column void times for columns with the same oven temperature profile before and after the experimental runs but with four different flow rates.

[0070] Figure 8 It is a graph showing the variation of a set of ASTM noise with the number of column void times for three different flow rates according to another experiment.

[0071] Figure 9 It is a flow chart showing an example of a method for gas chromatography (GC) of a sample according to another embodiment.

[0072] Figure 10 It is a set of chromatograms obtained for four different experimental runs according to the examples described herein.

[0073] Figure 11 It is a set of chromatograms obtained for four different experimental runs according to another example described herein.

[0074] Figure 12 It is a set of chromatograms obtained for three different experimental runs according to another example described herein. DETAILED DESCRIPTION OF THE INVENTION

[0075] In the context of the present disclosure, the term "analyte" generally refers to any sample molecule of interest to a researcher or user of gas chromatography (GC) - i.e., a molecule that one wishes to analyze (e.g., by chromatography or chromatography / mass spectrometry). The term "sample" or "sample matrix" refers to any substance known or suspected to contain an analyte. A sample can include a combination of an analyte and non-analytes. In this context, the term "non-analyte" or "non-analytical component" refers to a sample component that is not of interest to analyze because such a component has no analytical value and / or impairs (e.g., interferes with) the analysis of the desired analyte. Non-analytes can generally be any molecule that is not of interest, such as contaminants or impurities. Examples of non-analytes can include, but are not limited to, water, oil, solvents, or other media in which the desired analyte can be found, as well as stationary phase materials that have leaked from the chromatographic column.

[0076] As used herein, for convenience, the term "gas" encompasses vapors, as well as gases in which vapors, droplets, or particles can be entrained.

[0077] Figure 1FIG. 0 is a schematic diagram of an example of a gas chromatography (GC) system or apparatus 100 (also simply referred to as a gas chromatograph or GC) according to a representative embodiment. Those skilled in the art generally understand gas chromatography and the instruments used to implement gas chromatography. Therefore, for the purposes of facilitating an understanding of the subject matter disclosed herein, only a brief description of GC 100 and certain of its components is provided herein.

[0078] GC 100 may generally include a GC inlet (or GC inlet device) 104, a GC column 108, a heating device (or column heater) 112, and a detector 116. GC 100 may further include a sample introduction device (or sample syringe) 120 and a carrier gas source (or carrier gas supply device) 124. GC 100 may further include a system controller or computing device (or more simply, a controller) 128. A power supply 132 is also schematically shown, which may represent one or more devices configured to supply power to one or more power-consuming components of GC 100 (such as controller 128, heating device 112, etc.).

[0079] The sample introduction device 120 may be any device configured to inject a sample into the GC inlet 104. Sample injection may be performed on an automatic, semi-automatic, or manual basis. The sample introduction device 120 may include, for example, a manually operated syringe or a syringe as part of an autosampler (or "automatic sampler"). The source of the sample may be the syringe itself, or it may be one or more sample containers provided at the sample introduction device 120. In the latter case, the sample containers may be loaded on a turntable or other device that selects the desired sample to be injected into the GC column 108. The sample may also be introduced as a gas.

[0080] The carrier gas source 124 supplies a carrier gas flow to the GC inlet 104 via a carrier gas line at a regulated flow rate and / or pressure. The carrier gas source 124 may include, for example, a cylinder and a flow controller or pressure controller (such as one or more valves, one or more flow regulators, etc.). The carrier gas may be any gas suitable for use as an inert mobile phase to facilitate the transport of the sample through the GC column 108, as understood by those skilled in the art. Examples of carrier gases include, but are not limited to, helium, nitrogen, argon, and hydrogen. The carrier gas source 124 may also supply gases that do not flow through the column 108, such as the split vent outlet flow in a split / splitless inlet, the septum purge flow, etc., as understood by those skilled in the art.

[0081] The GC inlet 104 is configured to introduce a sample to be analyzed into the carrier gas stream and may also be configured to perform certain types of pre-column treatment of the sample / carrier gas mixture as understood by those skilled in the art. The GC inlet 104 may include respective ports that communicate with the sample introduction device 120, the carrier gas source 124, and the head of the column 108. The port that communicates with the sample introduction device 120 may include a septum that can be penetrated by a needle for injecting the sample and that can be re-self-sealing after the needle is removed. The GC inlet 104 may also include one or more internal chambers that communicate with such ports, as well as one or more outlets. The GC inlet 104 may also include local temperature control means.

[0082] The heating device 112 may have any configuration suitable for maintaining the column 108 at a desired temperature setting or for changing the temperature of the column 108 according to a desired (predetermined) temperature profile (i.e., temperature programming), for example to balance parameters such as elution time and measurement resolution. In some embodiments, the heating device 112 is configured to indirectly heat the column 108 by heating the internal space in which the column 108 is enclosed. For example, the column 108 may be mounted in a "GC oven". In other embodiments, the heating device 112 is configured to directly heat the column 108. For example, the column 108 may be mounted directly or in close proximity to the heating device 112, or the heating device 112 may include a resistive heating element wound around the column 108. In all such embodiments, the heating device 112 may be considered to be positioned in thermal contact with the column 108, i.e., positioned so as to effectively control the temperature of the column 108 with sufficient responsiveness for GC sample runs.

[0083] The GC 100 may also include means for actively cooling the column, such as a fan or other source of moving fluid sufficient to reduce the column temperature, a thermoelectric (e.g., Peltier) cooler, cryogenic fluids, and other cooling methods known to those skilled in the art.

[0084] Detector 116 can be any detector suitable for detecting separated bands (or "peaks") eluted from column 108. Examples of detectors include, but are not limited to, flame ionization detector (FID), thermal conductivity detector (TCD), electron capture detector (ECD), flame thermionic detector (FTD), flame photometric detector (FPD), etc. Generally, a wide variety of detectors can be used, and the illustrated detector 116 can represent a combination of two or more different types of detectors. In some embodiments, detector 116 is an analytical instrument (such as a mass spectrometer (MS), ion mobility spectrometer (IMS), etc.), or a part of an analytical instrument. Thus, in some embodiments, GC system 100 can be a hyphenated system, such as a GC-MS or GC-IMS system. Detector 116 can also schematically represent a data acquisition system, a display / readout device, and other components associated with generating chromatograms and spectra as understood by those skilled in the art.

[0085] The controller 128 can represent one or more modules that are configured to control, monitor, and / or time various functional aspects of the GC system 100, such as controlling the operation of the sample introduction device 120, the carrier gas source 124, the GC inlet 104, the heating device 112, and the detector 116, as well as controlling various gas flow rates, temperature, and pressure conditions. In particular, the controller 128 is configured to control the heating and cooling of the column 108 (by controlling the heating device 112 (and optionally also an active cooling device, as noted previously)) and the carrier gas flow (by controlling the carrier gas source 124), as further described herein. Thus, the controller 128 can include a programmable column temperature controller 134. The controller 128 can also be configured to receive detection signals from the detector 116 and perform other tasks related to data acquisition and signal analysis as needed to generate data (e.g., chromatograms) characterizing the analyzed sample. The controller 128 can include a non-transitory computer-readable medium that includes instructions for performing any of the methods disclosed herein. Depending on the need to perform control, monitoring, and / or timing operations, the controller 128 can include one or more types of hardware, firmware, and / or software, as well as one or more memories and databases. The controller 128 typically includes a main electronic processor that provides overall control and can include one or more electronic processors configured for dedicated control operations or specific signal processing tasks. The controller 128 can also include one or more types of user interface devices, such as user input devices (e.g., keypad, touch screen, mouse, etc.), user output devices (e.g., display screen, printer, visual indicator or alarm, audible indicator or alarm, etc.), a software-controlled graphical user interface (GUI), and a device for loading media readable by the electronic processor (e.g., logical instructions contained in software, data, etc.). The controller 128 can include an operating system (e.g., Microsoft software) for controlling and managing the various functions of the system controller. For all such purposes and functions, Figure 1 communication links (dashed lines) between the controller 128 and the Figure 1 various other components shown in are schematically depicted, and these communication links can be wired or wireless links. It will be understood that the controller 128 can communicate with other components not specifically shown in Figure 1 , such as various sensors (e.g., for measuring / monitoring temperature, pressure, flow rate, etc.). Figure 1 The solid lines in generally depict fluid flow and the various conduits that define or direct such fluid flow.

[0086] Figure 2FIG. 0 is a schematic illustration of GC column 108 and related components that are part of or define the sample flow path through GC 100. Column 108 has a column inlet 236 at one end that is in fluid communication (directly or indirectly) with GC inlet 104, and a column outlet 240 at the other end that is in fluid communication (directly or indirectly) with detector 116. Generally, column 108 can have any configuration now known or later developed. Column 108 is typically a small-bore tube made of glass or metal (e.g., on the order of tens or hundreds of micrometers (μm) in inner diameter). Typical column lengths range from 5 m to 100 m, while typical column inner diameters range from 50 μm to 530 μm. Column 108 can have an outer coating of polyimide or other material to strengthen and protect column 108. Column 108 includes a stationary phase suitable for GC that lines or coats the inner surface of column 108. As will be understood by those skilled in the art, the stationary phase can be, for example, a liquid or polymer layer that has a formulation effective for chromatographic separation and is loaded on an inert matrix.

[0087] Also as Figure 2 shown, all or a portion of column 108 and GC inlet 104 can be enclosed in housing 244. Housing 244 can include one or more doors that can access column 108, as well as other components and features located inside housing 244. When closed, housing 244 can be configured to be fluid-tight to prevent gas from leaking from the interior of the housing to the environment, and can provide thermal insulation between the interior of the housing and the environment. In some embodiments, housing 244 is or includes a temperature-programmable GC oven, and heating device 112 is configured to heat the interior of the oven through which column 108 extends. In other embodiments, heating device 112 can directly heat column 108 as described above. In some embodiments, housing 244 or the portion of housing 244 that encloses the interior space in which column 108 is located can include one or more outlets (which can be selectively opened and closed) that assist in controlling the heating and cooling of column 108. Also as Figure 2 shown, column 108 can be coiled into a single-loop or multi-loop configuration to accommodate the desired length between column inlet 236 and column outlet 240 while minimizing the size of housing 244. Column 108 can be coiled into a planar, cylindrical shape, etc. Column 108 can be configured in any additional way such that not all portions of column 108 cool at the same time or at the same rate. Additionally, it will be understood that Figure 2 the column 108 shown in Figure 1 can schematically represent two or more different columns arranged in series and / or parallel via suitable fluid connectors (fittings, tee connectors, etc.), and GC system 100 ( Figure 1 ) can be configured in some embodiments for multidimensional GC sample runs.

[0088] It will be understood that Figure 1 and Figure 2 are high-level schematic depictions of representative GC system 100 and related components. As will be understood by those skilled in the art, depending on how GC system 100 is configured for a given application, other components and features may be included according to the needs of the actual implementation, such as additional structures, devices, and electronics.

[0089] Referring to Figure 1 and Figure 2 , a general example of operating GC system 100 to analyze a sample is as follows. The carrier gas source 124 is operated to establish a carrier gas flow through the GC inlet 104, column 108, and detector 116 under the desired (predetermined) flow conditions (pressure, flow rate, etc.), which is referred to as column flow. The carrier gas source 124 may also provide flows to other parts of the GC system 100. The time period from the start of sample injection, followed by the sample flowing through the column 108 and the separated bands reaching the detector 116 (i.e., elution of the analytes of interest from the column) is referred to herein as the sample run time. In some cases, the column flow may be held constant or ramped throughout the sample run time. In other cases, a constant or ramped pressure may be maintained at the head of the column 108 throughout the sample run time. The heating device 112 is operated to heat the column 108 to a predetermined initial column temperature. The sample introduction device 120 is operated to inject the sample into the carrier gas stream flowing through the GC inlet 104 to produce a mixture of the sample and the carrier gas. The internal gas pressure at the head of the column 108 drives the sample / carrier gas mixture through the column 108, during which time the different analytes of the sample interact with the stationary phase in the column 108 with different degrees of affinity. This causes the different analytes to become separated from each other along the length of the column 108, which ultimately results in the different analytes eluting from the column outlet 240 and thus reaching the detector 116 at different times (i.e., in sequence - for example, first analyte A, then analyte B, then analyte C, etc.), where molecules of the same type of analyte (i.e., the same chemical compound) elute together as a "band" or "peak". The detector 116 detects the different analytes as they reach the detector 116 and operates according to a detection / measurement principle that depends on the type of detector employed (FID, MS, etc.). The detector 116 outputs electrical signals (analyte detection / measurement signals) to the controller 128, which processes and adjusts these signals as needed to produce a chromatogram, as will be understood by those skilled in the art.

[0090] During the sample run time, the heating device 112 is operated to maintain the column temperature at a predetermined or set point value, or to change the column temperature according to a predetermined temperature profile or program, as specified by the particular method being implemented. After the sample run time (i.e., after the analytes of interest have been separated and eluted from the column for that particular sample run), the column 108 is cooled in preparation for the next sample run. Cooling of the column 108 can be achieved by abruptly terminating the active operation of the heating device 112 or by controlling the heating device 112 to gradually ramp down the actively applied heat. The cooling of the column 108 can also be actively assisted by operating a cooling device such as a fan (i.e., forced air cooling), a thermoelectric (e.g., Peltier) device, or a cryogenic fluid (e.g., liquid nitrogen or carbon dioxide), or other methods known in the art. The time to cool the column 108 is referred to herein as the column cooling time.

[0091] During the sample run, the column 108 can reach a column temperature high enough to cause the stationary phase to start decomposing, resulting in a phenomenon known as "column bleed". Certain GC detectors (e.g., GCMS, FID) may be sensitive to these decomposition products. Due to their smooth and continuous elution during the sample run, the decomposition of the column stationary phase will cause an increase in the baseline signal of the sample run, which will reduce the signal-to-noise ratio of the detector. However, at the end of the sample run, some of these decomposition products will still be present in the column 108, and depending on how quickly and uniformly the column 108 is cooled and how quickly the temperature is ramped up in the next sample run, these products from the previous run may disrupt the baseline of the next sample run in a more significant manner.

[0092] If the column 108 is cooled gradually and uniformly after the sample run, the effect of column bleed from the previous sample run on the baseline of the next sample run will be small. Slow and uniform cooling allows the decomposition products to be evenly distributed along the length of the column 108. When the decomposition products become mobile again during the next sample run, they will elute in a smooth and continuous manner, which will result in a smooth increase in the baseline. However, if the column 108 is cooled very quickly (e.g., at a rate greater than 200 °C / min) and particularly asymmetrically, significant temperature gradients can form within the coil (or loop) of the column 108. These temperature gradients only persist for a short period of time, but during this time, the decomposition products, whose mobility is assisted by the carrier gas flow, can preferentially migrate and redeposit into the colder regions of the column 108. When the temperature is ramped up during the next sample run, these decomposition products may elute together with the sample analytes. Due to their sporadic or discontinuous positions in the column 108, the decomposition products cause an irregular-looking baseline perturbation rather than a smooth increase in the baseline level. In particular, the interference or oscillation of the baseline can be sufficiently pronounced to be observed as peaks (i.e., "ghost" peaks), which may lead to errors in peak identification or integration.

[0093] As noted, cooling column 108 more slowly than normal will reduce the formation of a thermal gradient in column 108, which thermal gradient formation can cause such carryover effects. However, such a solution can significantly increase the cooling time and thus reduce the sample analysis throughput. Another solution could be to bake column 108 to reduce the production of column bleed, but the baking process can take several hours and again undesirably increase the sample analysis throughput. Also, long exposure to high temperatures can reduce the effectiveness of the stationary phase.

[0094] In view of the foregoing considerations, according to one embodiment, a three-stage column cooling procedure is implemented to mitigate column bleed carryover. The three-stage column cooling procedure includes a first high-speed cooling ramp, followed by an isothermal hold (i.e., a dwell or hold time during which the column temperature is held at an isothermal dwell or intermediate temperature) followed by a second high-speed cooling ramp. The dwell temperature is cold enough such that the column phase does not significantly decompose but still warm enough to facilitate flushing away any decomposition products. In a non-limiting example, the dwell temperature is in the range of from about 20 °C to about 100 °C below the final column temperature. The flush time (the sum of the time of the first high-speed cooling ramp and the isothermal dwell time) is a predetermined period of time that effectively allows decomposition products to be flushed from column 108. In a non-limiting example, the flush time is in the range of from about 1 to about 4 times the void time of column 108. As used herein, the column void (or dead) time is the amount of time an analyte spends in the mobile phase (carrier gas) from the time the mobile phase is injected to the time it reaches detector 116, where the analyte is not retained by the stationary phase in column 108. In a non-limiting example, the flush time spans a period of time in the range of about 1 minute to 5 minutes.

[0095] Optionally, during the isothermal hold (dwell time), the column inlet pressure can be increased to accelerate the flushing of decomposition products by increasing the column flow. Increasing the column flow during the isothermal hold is useful for reducing the effective column void time and thus reducing the required flush time.

[0096] After the predetermined isothermal hold time, the high-speed cooling is restarted (i.e., the second cooling ramp is initiated) to return to the starting column temperature to prepare for the next sample run. Also, before or after the end of the predetermined isothermal hold time, the column flow rate (if increased during the isothermal hold as just described) is reduced back to the initial flow rate (e.g., by reducing the column inlet pressure) to prepare for the next sample run.

[0097] The first and second cooling ramps are described as "high speed" because their associated cooling rates are relatively fast. As a non-limiting example, the cooling rate implemented during any one or both of the first and second cooling ramps is in the range of 100 °C / min to 1000 °C / min. In some embodiments, the cooling rate of the first cooling ramp is greater than (faster than) the cooling rate of the second cooling ramp. In some embodiments, the duration of the first cooling ramp is less than (shorter than) the duration of the second cooling ramp.

[0098] Figure 3 An example of a column temperature program (or profile) 300 that can be repeated during consecutive operating cycles (sample run time plus column cooling time) of a GC system is shown, Figure 3 and two such cycles are shown. In particular, the column temperature program 300 is a plot of column temperature (°C) versus time (min). As described above, one operating cycle typically includes a sample run time followed by a column cooling time. During the sample run time, a sample is introduced into the carrier gas stream and thus driven through the GC column, the resulting separated fractions are eluted from the column and into the detector, and thus chromatographic data is acquired. The column cooling time corresponds to the period of time during which the column is cooled according to the embodiments disclosed herein and occurs after the analyte of interest has been eluted from the column for a particular sample run.

[0099] The column temperature program 300 begins with the column being heated to an initial column temperature 352, which is a relatively low temperature (e.g., between 30 °C and 100 °C). The column can be held at the initial column temperature 352 (which can typically be constant or slightly varying) for a relatively short period of time (e.g., a few minutes). After the initial column temperature 352 can be one or more heating ramps and isothermal holds. The final column temperature 360 is typically but not always the highest temperature during the run. In the example shown, the final column temperature 360 is 350 °C, while in other examples it can be greater than or equal to 350 °C. The column can be held at the final column temperature 360 for a relatively short period of time (e.g., a few minutes). The end of the period at the final column temperature 360 can correspond to the start of the cooling time, which can be referred to as the heat-cool transition point 364. The end of the sample run time can correspond to the heat-cool transition point 364, or the end of the sample run time can occur at some earlier point during the period at the final column temperature 360. The start of the sample run time can occur before, at, or after the transition point from the initial column temperature 352 to the heating ramp 356.

[0100] Figure 3Illustrates a relatively simple case where the heating portion (heating curve or heating program) of the column temperature program 300 includes a period at the initial column temperature 352, followed by a heating ramp 356, followed by a period at the final column temperature 360. More generally, it will be understood that the characteristics of the heating portion of the column temperature program 300 will depend on the parameters required by the specific chromatographic method being implemented for a given sample. Thus, for example, the heating portion of the column temperature program 300 can include two or more different heating ramps, which can have the same or different heating rates, and can or can not be separated by one or more isothermal hold times occurring at one or more intermediate temperatures between the initial column temperature 352 and the final column temperature 360.

[0101] The column cooling time begins at the heating-cooling transition point 364 and ends at the transition point where the initial column temperature 352 is reached again. As noted, in the present embodiment, the cooling portion of the column temperature program 300 is a three-stage column cooling program that includes a first cooling ramp 368, followed by an isothermal hold 372, and then followed by a second cooling ramp 376. In the example shown, the temperature of the isothermal hold 372 (i.e., the hold temperature) is 300 °C, while in other examples it can be greater than or less than 300 °C. The hold temperature and the hold time (the duration of the isothermal hold 372) can be determined in various ways, examples of which are described below.

[0102] The period during which the column is held at the initial column temperature 352 can be set as needed to provide a time for stabilizing the column conditions between the previous cooling time and the subsequent heating ramp 356 of the next sample run after a sample run.

[0103] Depending on the specific chromatographic method being implemented for a given sample, the column flow can be maintained constant (or substantially constant) or changed one or more times during the sample run. As noted above, in some embodiments, the column flow is increased during all or a portion of the period of the isothermal hold 372. Typically but not exclusively, the column flow is determined or controlled by the fluid pressure at the inlet or head of the column. Figure 3Shows an example of a pressure program (or profile) 384 that can be repeated during successive operating cycles (sample run plus column cool-down time) of a GC system. In particular, the pressure program 384 is a plot of column inlet pressure (psi) versus time (min). In the illustrated embodiment, the pressure program 384 includes an optional boost ramp 388 during the isothermal hold that increases the column inlet pressure from an initial pressure to an elevated pressure. Following the boost ramp 388 is a dwell pressure hold 392 during which the pressure is maintained at the elevated value. Following the dwell pressure hold 392 is a depressurization ramp 396 that reduces the column inlet pressure back to (reduces back to approximately) the initial pressure. The depressurization ramp 396 can be relatively steep, i.e., as a step-down. The boost ramp 388 can begin at or shortly after the start of the isothermal hold 372. The dwell pressure hold 392 can span all or a portion of the time period of the isothermal hold 372. The elevated pressure and the duration of the dwell pressure hold 392 can be determined in a variety of ways, examples of which are described below.

[0104] The initial pressure is the value of the column inlet pressure at the start of the boost ramp 388 and can be the same as or different from the column inlet pressure at the start of the sample run. As Figure 3 shown in the example of, the pressure program 384 can change the column inlet pressure at other times during the sample run, i.e., can include additional pressure ramps, steps, or holds other than those associated with the dwell pressure hold 392.

[0105] Figure 4 Is a flow chart 400 showing an example of a method for performing gas chromatography (GC) on a sample according to an embodiment of the present disclosure. As an initial step, the flow of carrier gas through the GC column is initiated (step 402), and heating of the GC column is initiated (step 404). The heating of the GC column can be initiated (e.g., to a low temperature) before the flow of carrier gas through the GC column begins. Thus, Figure 4The order of steps 402 and 404 shown is not intended to limit the order of initiation of carrier gas flow and column heating. After the carrier gas flow and column heating are initiated, a sample is then injected (step 406) into the flowing carrier gas to produce a mixture of the sample and the carrier gas, and during a period of time herein referred to as the sample run time, the mixture is passed through the GC column to the detector to obtain chromatographic data from the sample. When the mixture passes through the GC column, heating step 404 may be required to increase the column temperature of the GC column from an initial temperature to a maximum temperature. After the sample run time, the GC column is cooled according to a cooling program. The cooling program may include a first cooling ramp (step 408) through which the column temperature is reduced from the maximum temperature to a hold temperature; a subsequent isothermal hold or hold period (step 410) during which the column temperature is maintained at a substantially constant hold temperature; and a subsequent second cooling ramp (step 412) through which the column temperature is reduced back to the initial temperature. Optionally, during the isothermal hold 410 as described above, the fluid flow rate through the GC column may be increased.

[0106] Figure 4 The flowchart 400 shown may also represent an apparatus or a system (e.g., a GC system) capable of performing the method shown. The controller of the apparatus or system (e.g., the controller 128 described herein and Figure 1 shown) may be configured to perform (i.e., control other components of the apparatus or system to perform) all or part of one or more steps of the method. For example, the controller may be configured to control a carrier gas source to cause the carrier gas to flow at a predetermined flow rate, control a sample injector to inject a predetermined amount of sample material into the carrier gas flow at a predetermined time, control a heating device to heat the GC column according to a predetermined heating program, and control the heating device (or both the heating device and an active cooling device) to reduce the temperature of the GC column according to a predetermined cooling program.

[0107] Example 1

[0108] An Agilent Technologies, Inc. model 19091J-413 column (HP-5 320 μm ID × 30 m × 0.25 μm film thickness) was installed in the same as described above and Figure 1 and 2In a GC system consistent with the system shown, the GC system is equipped with an FID. A carrier gas (helium) without sample material is run through the column at a constant flow rate of 1 mL / min. That is, the experimental run evaluated in this example is a "blank" run. The temperature program 300 includes an initial temperature 352 of 65 °C, a heating ramp 356 of 150 °C / min, and a final temperature 360 of 350 °C. Although the ramp rate 356 of 150 °C / min exceeds the ramp rate typically used for columns of these dimensions, it helps to exaggerate the problem, making it easier to measure.

[0109] Figure 5 Is a set of three chromatograms obtained from three consecutive sample runs using a GC system. In each case, the chromatogram shown is that of the subsequent run, showing the noise generated on the baseline due to column bleed carryover from the previous run. In the top chromatogram, the extent of column bleed carryover is confirmed if the techniques described herein are not used. The baseline includes distinct peaks, especially in the region from 1.5 min to 3.5 min. If sample analytes were injected and eluted within this time frame, it could disrupt identification and quantification.

[0110] If the column is allowed to flush at a hold temperature of 300 °C after the first sample run, then for the next run, the noise is significantly reduced with a given total flush time of 2 minutes (the first rapid cool time plus the isothermal hold time), as is evident from the comparison of the top chromatogram with the middle chromatogram in Figure 5 For a column of this size at 300 °C and a He flow rate of 1 mL / min, the void time is approximately 1.8 minutes. Flushing for 2 minutes is approximately 1.1 void times. If, in addition to holding at 300 °C, the column pressure is increased only during the isothermal hold time to a hold flow rate of 3 mL / min (0.85 min void time), a comparable degree of noise reduction can be achieved with a flush time of only 1 minute, as is evident from the bottom chromatogram in Figure 5 Is evident from the bottom chromatogram in

[0111] Example 2 - Determination of Hold Temperature

[0112] The optimal hold temperature depends largely on the type and size of the stationary phase on the column and the final temperature of the column. It can be experimentally determined by observing the extent to which column bleed causes baseline interference in subsequent runs (the measurement method used in the following examples is American Society for Testing and Materials (ASTM) Noise), obtained by flushing for 1 to 2 void times at various hold temperatures after the end of the previous run and between rapid cooling.

[0113] If the selected hold temperature is too cold, the bleed products that have been generated during the sample run will not be very mobile and will not be easily flushed. On the other hand, if the selected hold temperature is too hot, the phase on the column will continue to decompose significantly during the flush period, which will also result in poor column clean-up. At the optimum point, these two requirements are well balanced. This is shown in Figure 6 which is a plot of a set of ASTM noise versus hold temperature for four different flush times for a DB-5ms column and a method that includes a final temperature of 350 °C. For this column and this method condition, a hold temperature that is approximately 50 °C below the final temperature (i.e., 300 °C) is near optimum.

[0114] Example 3 - Determination of Hold Time

[0115] The hold time is the time spent isothermally at the hold temperature. To generalize across a variety of method configurations, it is useful to discuss the total flush time (the sum of the first cool time and the hold time) in terms of the number of column void times (N 空隙 ) rather than absolute time. This is because the rate at which bleed particles can be flushed out of the system is directly related to the flow rate through the column. The number of column void times during the flush can be expressed as:

[0116]

[0117] Figure 7 is a plot of a set of ASTM noise versus the number of column void times for an HP-1 column that was run at the same oven thermal profile before and after an experimental run but with four different flow rates. When the curves are plotted in terms of the number of void times, they show a similar trend, namely that most of the benefit in reducing noise is achieved after one void time. This is because the hold temperature was chosen such that the bleed products are sufficiently mobile. Thus, according to one embodiment, it is recommended that the hold time be selected such that the total flush time is in the range of about 1 to about 4 void times.

[0118] Example 4 - Determination of Hold Pressure / Flow

[0119] As previously noted, it is optional to increase the flow rate through the column during the isothermal hold time. The effect of increasing the flow rate is to flush the system more quickly because the column void time is reduced. This is more easily visualized by again considering the flush time in terms of the number of void times.

[0120] Figure 8is a graph showing the variation of a set of ASTM noise with the number of column void times for three different hold flow rates. In this example, an HP-5 320 μm × 30 m × 0.25 μm column was ramped from 65 °C to 350 °C at 150 °C / min. The flow rate during the run was 1 ml / min of helium. After the run was completed, the column was cooled to a hold temperature of 300 °C. Once the isothermal hold temperature was reached, the flow rate was increased to Figure 8 the value indicated on the curve of Figure 8 . Using the number of effective void times calculated by averaging the flow curve over the flush period, the noise curves can be shown to overlay each other. This means that for a flow rate of, for example, 3 mL / min, where the void time is approximately half that at 1 mL / min, the same baseline noise reduction can be achieved in half the hold time.

[0121] According to another embodiment, column bleed carryover can be mitigated by significantly reducing (slowing down) or even aborting (stopping) the column flow for a predetermined short period of time (e.g., about 15 seconds to 30 seconds), which at least partially overlaps with the period of any form of cooling where column bleed occurs and a significant thermal gradient develops along the entire length of column 108. This reduction or abortion of the column flow can start at a point in time before the column cooling begins and can end at a point in time while the column cooling is still in progress or after the column cooling is completed. Reducing or aborting the carrier gas flow through column 108 at such a time can significantly reduce the mobility of the decomposition products so that they do not redistribute unevenly in column 108 during cooling. After the cooling is completed (or the column temperature is low enough for the decomposition products to remain immobilized), the column flow can be restored for normal purposes (e.g., purging the gas lines to prepare for the next sample run). If the carrier gas flow through parts of the GC system 100 other than column 108 (e.g., the flow through the split vent trap or the septum purge flow) is controlled independently of the column flow, it is not necessarily required to stop or slow down such flows. Additionally, the gas flow through the detector 116 (e.g., the detector make-up flow, etc.), which is also not part of the column flow, does not necessarily have to be stopped or slowed down either.

[0122] Figure 9 is a flow chart 900 showing an example of a method for gas chromatography (GC) of a sample according to an embodiment of the present disclosure. As an initial step, the carrier gas flow through the GC column is started at an initial (or first or normal) flow rate (step 902), and the heating of the GC column is started (step 904). The heating of the GC column can be started (e.g., to a low temperature) before the carrier gas flow through the GC column begins. Thus, Figure 9The order of steps 902 and 904 shown is not intended to limit the order of initiation of carrier gas flow and column heating. After the carrier gas flow and column heating are initiated, the sample is then injected (step 906) into the flowing carrier gas to produce a mixture of the sample and the carrier gas, and during a period of time herein referred to as the sample run time, the mixture is flowed through the GC column to a detector to obtain chromatographic data from the sample. During the sample run time, heating of the GC column can be carried out in order to maintain the GC column at a predetermined temperature or to change the column temperature according to a predetermined temperature profile, depending on the particular method being implemented.

[0123] Once the analysis is complete, following the sample run time is a predetermined period during which the column flow is reduced from an initial flow rate to a reduced (or second) flow rate (step 908) in order to reduce the mobility of the stationary phase decomposition products prior to initiating column cooling. In some embodiments, the reduced flow rate can be a zero flow rate, i.e., reducing the flow rate may require completely aborting (stopping) the column flow. Following this waiting time for the slowed or stopped flow is a cooling time during which the GC column can be cooled (step 910). As described herein, the cooling can be carried out passively or can be assisted by an active cooling process. The flow continues at a reduced rate or completely stops for part or all of this cooling time (step 912) to ensure that the decomposition products continue to have very little mobility. Once the cooling is complete, if the flow has not already been so restored, the flow can be restored to its pre-run conditions (e.g., the method can return to step 902).

[0124] The appropriate predetermined time to minimize the mobility of the stationary phase decomposition products during cooling depends on column dimensions (e.g., inner diameter (ID) and length) and certain method parameters (e.g., carrier gas type, flow rate, column temperature). It can be determined experimentally. One method is to introduce a continuous material flow into the carrier gas stream to which the detector is sensitive (e.g., methane for FID). Once the flow is established, the column pressure can be set to zero, and the time at which the baseline shows a downward step change corresponds to the minimum time required to slow or stop the flow. Another option is to conduct a series of experiments and observe the magnitude of the baseline interference for different slowdown or stop times. For example, in an initial experiment, the column flow is maintained at its normal level after each run, and the early baselines in successive runs are examined to discern the magnitude of the problem. In subsequent experiments, the time for reducing or aborting the column flow is increased, and the effect on the runs following each previous run is observed. When the effect has sufficiently diminished, no further increase in time is required. As a non-limiting example, for a 30 m (length) × 320 μm (ID) × 0.25 μm (phase thickness) column, the required slowdown or stop time is typically about 15 to 30 seconds.

[0125] As discussed above, an alternative to completely stopping the flow prior to the initial cooling period to reduce column bleed effects is to slow the flow both before and during cooling. The flow must be slow enough so that the decomposition products are reasonably immobilized. It has been shown that reducing the flow rate by 80% (i.e., reducing to 20% of the normal flow rate) significantly improves the column bleed carryover effect.

[0126] Ideally, for a rapid-cooling oven, the decomposition products should be substantially immobilized at the start of cooling. This requires that the inlet pressure at the head of the column be the same (or nearly the same) as the outlet pressure. For a simple GC system with a column having one end connected to the inlet and the other end connected to an atmospheric pressure detector, this can be achieved by setting the inlet pressure to zero gauge pressure (or nearly zero gauge pressure) or by setting the flow controller to zero (or nearly zero). More complex systems (such as those involving post-column backflushing with pressure control on both the inlet and outlet sides of the column) require that the pressure controller connected to the outlet of the column be set equal to (or nearly equal to) the inlet pressure.

[0127] Although not desirable as it increases the cycle time, the column flow can be aborted or reduced for a period of time. That is, the carrier gas flow rate through the column can be ramped down according to a predetermined reduced flow rate (e.g., about 30 mL / min / min) until the column flow reaches zero or a desired lower value rather than stopping instantaneously or in a stepwise fashion. Similarly, this condition of no flow or reduced flow can be maintained for a predetermined period of time both before and during cooling.

[0128] After the cooling time, i.e., after the GC column has been cooled to the desired temperature, full flow can be restored (if not already restored during cooling) and heating of the GC column can be resumed, i.e., steps 902 and 904 can be repeated to prepare for the next sample run. Thus, another sample can be injected (step 906) into the carrier gas stream, and the remaining steps of the method can be carried out as described herein. The method can be repeated for any number of additional sample runs, where column bleed carryover is minimized due to the control of column flow during the column cooling time as described herein.

[0129] Figure 9 The flowchart 900 shown can also represent an apparatus or system (e.g., a GC system) capable of performing the method shown. The controller of the apparatus or system (e.g., as described herein and Figure 1The controller 128) shown herein can be configured to perform (i.e., control other components of the device or system to perform) all or part of one or more steps of the method. For example, the controller can be configured to control the carrier gas source to cause the carrier gas and the sample to flow through the GC column and reach the detector, control the heating device to heat the GC column to a predetermined temperature or heat the GC column according to a predetermined temperature profile during sample run, control the heating device to suspend heating the GC column during the cooling time after the carrier gas and the sample flow through the GC column and reach the detector, control any active column cooling device provided, and control the carrier gas source to reduce or suspend the flow of carrier gas through the GC column at a predetermined start time and duration. The controller can also be configured to receive signals output from the detector to obtain chromatographic data from the sample during the sample run time.

[0130] Evaluation of the method disclosed herein has demonstrated that compared to conventional methods in which the carrier gas flow does not stop or slow down during cooling of the column 108, peak-like features in the signal attributable to elution and detection of decomposition products are eliminated or reduced.

[0131] Example 5

[0132] An Agilent Technologies, Inc. model 19091J-413 column (320 μm ID × 30 m × 0.25 μm phase film thickness) was installed in a GC system consistent with the system described above and Figure 1 and 2 shown herein. The GC system was equipped with an FID. A carrier gas (helium) without sample material was run through the column at a constant flow rate of 3 mL / min, i.e., the experimental run evaluated in this example was a "blank" run. The column length was 30 m. Typically for a column of this length, the GC system would be programmed to perform a column temperature rise of less than 20 °C / min. However, for this experiment, the GC system was programmed to perform an extremely fast column temperature rise of 150 °C / min to exaggerate the column bleed carryover problem and thus enhance the evaluation. Specifically, for each experimental run, when helium flowed through the column at 3 mL / min, the column temperature was held at 65 °C for 1 min, then the column temperature was ramped up to 315 °C at a rate of 150 °C / min, then held at 315 °C for 3 minutes, plus the period of pressure decay.

[0133] Figure 10is a set of chromatograms showing the effect on the baseline of subsequent runs of performing the method as described above for four different pressure decay curves. These are blank runs (meaning no sample was injected) to make it easier to observe the detector baseline. The FID signal in picoamps (pA) is tracked over elapsed time in minutes (min) for each subsequent run. Oscillations in the detector signal observed in the right hand region of these chromatograms indicate carryover problems, and the approximate peak-to-peak measurements of the degree of oscillation are noted for each chromatogram. The top chromatogram is the result of a "baseline" run in which the helium gas flow did not stop at the end of the previous run, i.e., a conventional method run. As Figure 10 indicated, the measured detector signal oscillation was 2.52 pA peak-to-peak. The second, third, and fourth chromatograms are the result of reducing the helium gas flow rate to 0 mL / min (no flow) at a rate of -30 (mL / min) / min, then holding that no-flow condition (0 mL / min) for different amounts of time and then restoring to helium gas flow. Specifically, the no-flow condition was held for 0 minutes, 0.25 minutes, and 0.125 minutes, respectively, as Figure 10 indicated. The runs in which the helium gas flow was stopped produced measured detector signals of 1.21 pA peak-to-peak, 0.36 pA peak-to-peak, and 0.58 pA peak-to-peak, respectively, as Figure 10 indicated. Thus, Figure 10 demonstrates the adverse column bleed effect and the effectiveness of reducing and stopping column flow prior to column cooling in reducing column bleed carryover according to the method disclosed herein.

[0134] Example 6

[0135] This example uses the same experimental conditions as indicated in Example 5 above, except for a more typical temperature ramp of 10 °C / min rather than 150 °C / min.

[0136] Figure 11 is a set of chromatograms obtained for four different experimental runs under the conditions indicated above. As in Example 5, the top chromatogram is the result of a baseline run in which the helium gas flow did not stop. As Figure 11 indicated, the measured detector signal was 0.186 pA peak-to-peak. As in Example 5, the second, third, and fourth chromatograms are the result of reducing the helium gas flow through the column to 0 mL / min (no flow) at a rate of -30 (mL / min) / min, then holding that no-flow condition (0 mL / min) for 0 min, 0.25 min, and 0.125 min, respectively, as Figure 11 indicated. The runs in which the helium gas flow was stopped produced measured detector signals of 0.074 pA peak-to-peak, 0.046 pA peak-to-peak, and 0.056 pA peak-to-peak, respectively,Figure 11 as indicated. Thus, Figure 11 further demonstrates the adverse column bleed effect and the effectiveness of reducing and stopping the carrier gas flow through the column during column cooling in reducing column bleed carryover according to the methods disclosed herein.

[0137] Example 7

[0138] This example uses the same experimental conditions as indicated in Example 5 above.

[0139] Figure 12 is a set of chromatograms obtained for three different experimental runs under the conditions indicated above. As in Example 5, the top chromatogram is the result of a baseline run in which the helium flow was not slowed and was maintained at 3 mL / min during and after the run. The measured detector signal was 5.1 pA peak-to-peak. In the second and third chromatograms, the He flow was slowed to 0.5 mL / min and 0.1 mL / min, respectively, for 0.5 min after the run ended and before cooling began. The runs in which the helium flow was slowed produced measured detector signals of 3.2 pA peak-to-peak and 3.2 pA peak-to-peak, respectively. Thus, Figure 12 further demonstrates the adverse column bleed effect and the effectiveness of reducing the carrier gas flow through the column before and during column cooling in reducing column bleed carryover and its adverse effects according to the methods disclosed herein.

[0140] Exemplary Embodiments

[0141] Exemplary embodiments provided in accordance with the presently disclosed subject matter include, but are not limited to, the following:

[0142] 1. A method for performing gas chromatography (GC) on a sample, the method comprising: flowing a carrier gas through a GC column; heating the GC column according to a heating program during a sample run time, the heating program including raising the column temperature of the GC column from an initial temperature to a final temperature; injecting the sample into the flowing carrier gas during the sample run time to produce a mixture of the sample and the carrier gas, and flowing the mixture through the GC column; and cooling the GC column according to a cooling program after the sample run time, the cooling program including: reducing the column temperature from the final temperature to a hold temperature; maintaining the column temperature at the hold temperature for an isothermal hold time; and after the isothermal hold time, reducing the column temperature from the hold temperature to the initial temperature.

[0143] 2. The method of embodiment 1, wherein the hold temperature is a temperature that is cold enough to substantially avoid decomposition of the stationary phase of the GC column phase and warm enough to facilitate flushing out decomposition products present in the GC column before the sample run time.

[0144] 3. The method of embodiment 1, wherein the hold temperature ranges from about 20 °C to about 100 °C below the final temperature.

[0145] 4. The method of embodiment 1, wherein the isothermal hold time is a period of time that is effective to flush decomposition products present in the GC column out of the GC column prior to the sample run time.

[0146] 5. The method of embodiment 1, comprising defining a flush time as the sum of the duration of the decrease in column temperature from the final temperature to the hold temperature and the isothermal hold time, wherein the flush time is selected from the group consisting of: a period of time in the range from about 1-fold to about 4-fold of the void time of the GC column; and a period of time in the range from about 1 minute to 5 minutes.

[0147] 6. The method of embodiment 1, wherein the decrease in column temperature from the final temperature to the hold temperature, or the decrease in column temperature from the hold temperature to the initial temperature, or both, is carried out at a cooling rate in the range from 100 °C / min to 1000 °C / min.

[0148] 7. The method of embodiment 1, wherein the decrease in column temperature from the final temperature to the hold temperature is carried out at a first cooling rate, the decrease in column temperature from the hold temperature to the initial temperature is carried out at a second cooling rate, and the first cooling rate is greater than the second cooling rate.

[0149] 8. The method of embodiment 1, comprising increasing the column flow rate from an initial flow rate to an elevated flow rate at or after the start time of maintaining the column temperature at the hold temperature for the isothermal hold time, and maintaining the column flow rate at the elevated flow rate for a flow rate hold time that spans at least a portion of the isothermal hold time.

[0150] 9. The method of embodiment 8, wherein increasing the column flow rate comprises increasing the column inlet pressure.

[0151] 10. The method of embodiment 1, comprising flowing the mixture from the GC column to a detector during the sample run time to obtain chromatographic data from the sample.

[0152] 11. The method of embodiment 1, wherein cooling the GC column according to the cooling program is carried out after the analyte of interest has been eluted from the column.

[0153] 12. A gas chromatography (GC) system comprising: a GC column; a carrier gas source configured to cause a mixture of a sample and a carrier gas to flow through the GC column; a heating device configured to heat the GC column; and a controller configured to: control the carrier gas source to cause the mixture to flow through the GC column during a sample run time; control the heating device to heat the GC column according to a heating program during the sample run time, the heating program including increasing the column temperature of the GC column from an initial temperature to a final temperature; and control the heating device to cool the GC column according to a cooling program after the sample run time, the cooling program including: reducing the column temperature from the final temperature to a hold temperature; maintaining the column temperature at the hold temperature for an isothermal hold time; and after the isothermal hold time, reducing the column temperature from the hold temperature to the initial temperature.

[0154] 13. The GC system of embodiment 12, wherein the controller is configured to maintain the hold temperature in a range from about 20 °C to about 100 °C below the final temperature.

[0155] 14. The GC system of embodiment 12, wherein the flush time is defined as the sum of the duration of reducing the column temperature from the final temperature to the hold temperature and the isothermal hold time, and wherein the controller is configured to control the heating device such that the flush time is selected from the group consisting of: a time period in a range from about 1 times to about 4 times the void time of the GC column; and a time period in a range from about 1 minute to 5 minutes.

[0156] 15. The GC system of embodiment 12, wherein the controller is configured to control the heating device such that the column temperature is reduced from the final temperature to the hold temperature, or the column temperature is reduced from the hold temperature to the initial temperature, or both of the foregoing, at a cooling rate in a range from 100 °C / min to 1000 °C / min.

[0157] 16. The GC system of embodiment 12, wherein the controller is configured to control the heating device such that the column temperature is reduced from the final temperature to the hold temperature at a first cooling rate, the column temperature is reduced from the hold temperature to the initial temperature at a second cooling rate, and the first cooling rate is greater than the second cooling rate.

[0158] 17. The GC system of embodiment 12, wherein the controller is configured to: increase the column flow rate from an initial flow rate to an elevated flow rate at or after the start time of maintaining the column temperature at the hold temperature for the isothermal hold time, and maintain the flow rate at the elevated flow rate for a flow rate hold time that spans at least a portion of the isothermal hold time.

[0159] 18. The GC system of embodiment 12 includes a cooling device configured to actively cool the GC column, wherein the controller is configured to control the cooling device to cool the GC column according to the cooling program after the sample run time.

[0160] 19. The GC system of embodiment 12 includes components selected from the group consisting of: a syringe configured to inject a sample into a carrier gas stream to produce a mixture; a detector configured to detect an analyte of the mixture flowing out of the column outlet; and both of the foregoing.

[0161] 20. The GC system of embodiment 12 includes a detector configured to detect an analyte of the mixture flowing out of the column outlet, wherein the controller is configured to receive a signal output from the detector to obtain chromatographic data from the sample.

[0162] 21. A non - transitory computer - readable medium having instructions stored thereon that, when executed by a processor, control or perform the cooling of a GC column according to the method of embodiment 1.

[0163] 22. A method for performing gas chromatography (GC) on a sample, the method comprising: flowing a carrier gas through a GC column; during a sample run, heating the GC column to a predetermined temperature or heating the GC column according to a predetermined temperature profile; during the sample run time, injecting the sample into the flowing carrier gas to produce a mixture of the sample and the carrier gas and flowing the mixture through the GC column; after the sample run time, cooling the GC column during a cooling time; and during at least an initial portion of the cooling time, reducing or terminating the flow of the carrier gas through the GC column.

[0164] 23. The method of embodiment 22 includes starting to reduce or terminate the flow of the carrier gas through the GC column before cooling the GC column.

[0165] 24. The method of embodiment 22, wherein the mixture flows through the GC column at an initial flow rate before reducing or terminating the flow of the carrier gas through the GC column, and further includes, after a predetermined portion of the cooling time, restoring the flow of the carrier gas through the GC column to the initial flow rate.

[0166] 25. The method of embodiment 22, wherein the mixture flows through the GC column at an initial flow rate before reducing or terminating the flow of the carrier gas through the GC column, and further includes cooling the GC column to at least a predetermined reduced column temperature during the cooling time and then re - flowing the carrier gas through the GC column at the initial rate.

[0167] 26. The method of embodiment 22, wherein reducing or terminating the flow of the carrier gas comprises reducing the flow rate of the carrier gas until the flow rate is at a predetermined reduced flow rate or zero flow rate, and maintaining the flow rate at the reduced flow rate or zero flow rate for a period of time equal to or greater than zero minutes.

[0168] 27. A gas chromatography (GC) system comprising: a GC column; a carrier gas source configured to cause a mixture of a sample and a carrier gas to flow through the GC column; a heating device configured to heat the GC column; and a controller configured to: control the carrier gas source to cause the mixture to flow through the GC column and reach a detector; control the heating device to heat the GC column to a predetermined temperature or heat the GC column according to a predetermined temperature profile during a sample run; control the heating device to terminate heating the GC column during a cooling period after the sample run time; and control the carrier gas source or a flow regulator between the carrier gas source and the GC column to reduce or terminate the flow of the carrier gas through the GC column during at least an initial portion of the cooling period.

[0169] 28. The GC system of embodiment 27, wherein the controller is configured to begin reducing or terminating the flow of the carrier gas through the GC column before cooling the GC column.

[0170] 29. The GC system of embodiment 27, comprising a cooling device configured to actively cool the GC column, wherein the controller is configured to control the cooling device to cool the GC column during the cooling period.

[0171] 30. The GC system of embodiment 27, comprising components selected from the group consisting of: a syringe configured to inject a sample into the carrier gas stream to produce a mixture; a detector configured to detect an analyte of the mixture flowing out of the column outlet; and both of the foregoing.

[0172] 31. The GC system of embodiment 27, comprising a detector configured to detect an analyte of the mixture flowing out of the column outlet, wherein the controller is configured to receive a signal output from the detector to obtain chromatographic data from the sample.

[0173] 32. A non-transitory computer-readable medium having instructions stored thereon that, when executed by a processor, control or perform reducing or terminating the flow of the carrier gas through the GC column according to the method of embodiment 22.

[0174] It will be understood that one or more of the processes, sub-processes, and process steps described herein can be performed on one or more electronic or numerically controlled devices by hardware, firmware, software, or a combination of two or more of the foregoing. The software can be present in a suitable electronic processing component or system (e.g., like,Figure 1 in the software memory (not shown) of the system controller 128 schematically depicted. The software memory may include an ordered list of executable instructions for implementing logical functions (i.e., "logic" that may be implemented in digital form or in analog form, the digital form such as digital circuitry or source code, and the analog form such as an analog source, such as an analog electrical, sound, or video signal). These instructions may be executed within a processing module that includes, for example, one or more microprocessors, general-purpose processors, processor combinations, digital signal processors (DSPs), or application-specific integrated circuits (ASICs). Additionally, the schematic depicts a logical partitioning of functions having physical (hardware and / or software) implementations, and these implementations are not limited by the architecture or the physical layout of these functions. Examples of the systems described herein may be implemented in a variety of configurations and operate in a single hardware / software unit or as hardware / software components in separate multiple hardware / software units.

[0175] These executable instructions may be implemented as a computer program product having instructions stored therein that, when executed by a processing module of an electronic system (e.g., Figure 1 the system controller 128 therein), direct the electronic system to execute these instructions. The computer program product may optionally be contained in any non-transitory computer-readable storage medium for use by or in connection with an instruction execution system, apparatus, or device, such as an electronically based computer system, a processor-containing system, or other system that can selectively obtain instructions from and execute the instructions of the instruction execution system, apparatus, or device. In the context of the present disclosure, a computer-readable storage medium is any non-transitory device that can store a program for use by or in connection with an instruction execution system, apparatus, or device. The non-transitory computer-readable storage medium may optionally be, for example, an electronic, magnetic, optical, electromagnetic, infrared, or semiconductor system, apparatus, or device. A non-exhaustive list of more specific examples of non-transitory computer-readable media includes: electrical connectors having one or more wires (electronic); portable computer disks (magnetic); random access memory (electronic); read-only memory (electronic); erasable programmable read-only memory, such as flash memory (electronic); optical disk memories, such as CD-ROM, CD-R, CD-RW (optical); and digital versatile disc memories, i.e., DVDs (optical). Note that the non-transitory computer-readable storage medium may even be paper or other suitable medium of a printed program, since the program can be electronically captured via, for example, optical scanning of the paper or other medium and then compiled, interpreted, or otherwise processed in a suitable manner if necessary and then stored in a computer memory or machine memory.

[0176] It will also be understood that the terms "in signal communication" or "in electrical communication" as used herein mean that two or more systems, devices, components, modules, or sub-modules are capable of communicating with each other via signals traveling in a signal path of some type. These signals can be communication, power, data, or energy signals that can convey information, power, or energy from a first system, device, component, module, or sub-module to a second system, device, component, module, or sub-module along a signal path between the first and second systems, devices, components, modules, or sub-modules. These signal paths can include physical, electrical, magnetic, electromagnetic, electro-chemical, optical, wired, or wireless connections. These signal paths can also include additional systems, devices, components, modules, or sub-modules between the first system, device, component, module, or sub-module and the second system, device, component, module, or sub-module.

[0177] More generally, terms such as "communicate" and "communicate with" (e.g., a first component "communicates with" a second component) are used herein to indicate a structural, functional, mechanical, electrical, signal, optical, magnetic, electromagnetic, ionic, or fluid relationship between two or more components or elements. Thus, the fact that a first component is said to communicate with a second component is not intended to exclude the possibility of additional components existing between and / or operably associated or engaged with the first and second components.

[0178] It will be understood that various aspects or details of the present invention may be changed without departing from the scope of the invention. Additionally, the foregoing description is for illustrative purposes only and not for purposes of limitation - the invention is defined by the claims.

Claims

1. A method for performing gas chromatography (GC) on a sample, the method comprising: Pass the carrier gas through the GC column; During the sample run time, heating the GC column according to a heating program, the heating program comprising increasing the column temperature of the GC column from an initial temperature to a final temperature; During the sample run time, injecting the sample into flowing carrier gas to produce a mixture of the sample and the carrier gas, and flowing the mixture through the GC column; and After the sample run time, the GC column was cooled according to a cooling program comprising: The column temperature is lowered from this final temperature to the dwell temperature; maintaining the column temperature at the dwell temperature for the isothermal dwell time; and After the isothermal dwell time, the column temperature is lowered from the dwell temperature to the initial temperature, Wherein the isothermal dwell time is a period of time effective to allow decomposition products present in the GC column prior to the sample run time to be flushed from the GC column.

2. The method of claim 1 , comprising defining a purge time as the sum of the duration over which the column temperature reduction from the final temperature to the dwell temperature occurs and the isothermal dwell time, wherein the purge time is selected from the group consisting of: a time period within a range from 1 to 4 times the void time of the GC column; and a time period within a range from 1 minute to 5 minutes, wherein the void time is the amount of time an analyte spends in a carrier gas from the time it is injected into the carrier gas to the time it reaches a detector, wherein the analyte is not retained by a stationary phase in the GC column.

3. The method according to claim 1, wherein the column temperature is decreased from the final temperature to the dwell temperature, or the column temperature is decreased from the dwell temperature to the initial temperature, or both, at a cooling rate ranging from 100°C / min to 1000°C / min.

4. The method according to claim 1, wherein the column temperature is decreased from the final temperature to the dwell temperature at a first cooling rate, the column temperature is decreased from the dwell temperature to the initial temperature at a second cooling rate, and the first cooling rate is greater than the second cooling rate.

5. The method of claim 1 , comprising increasing the column flow rate from an initial flow rate to an elevated flow rate at or after the start time of maintaining the column temperature at the dwell temperature for the isothermal dwell time, and maintaining the column flow rate at the elevated flow rate for a flow rate holding time that spans at least a portion of the isothermal dwell time. The method of claim 5 , wherein increasing the column flow rate comprises increasing the column inlet pressure.

7. The method of claim 1, comprising flowing the mixture from the GC column to a detector during the sample run time to acquire chromatographic data from the sample.

8. The method of claim 1, wherein cooling the GC column according to the cooling program is performed after the analyte of interest has been eluted from the column.

9. The method according to claim 1, comprising: During at least an initial portion of the cooling procedure, the flow of carrier gas through the GC column is reduced or stopped.

10. A gas chromatography (GC) system comprising: GC columns; a carrier gas source configured to flow a mixture of sample and carrier gas through the GC column; a heating device configured to heat the GC column; as well as A controller configured to: controlling the carrier gas source to flow the mixture through the GC column during a sample run time; controlling the heating device to heat the GC column according to a heating program during the sample run time, the heating program comprising increasing the column temperature of the GC column from an initial temperature to a final temperature; and controlling the heating device to cool the GC column after the sample run time according to a cooling program comprising: The column temperature is lowered from this final temperature to the dwell temperature; maintaining the column temperature at the dwell temperature for the isothermal dwell time; and After the isothermal dwell time, the column temperature is lowered from the dwell temperature to the initial temperature, Wherein the isothermal dwell time is a period of time effective to allow decomposition products present in the GC column prior to the sample run time to be flushed from the GC column.

11. The GC system of claim 10 , wherein the purge time is defined as the sum of the duration over which a decrease in column temperature from the final temperature to the dwell temperature occurs and the isothermal dwell time, wherein the controller is configured to control the heating device so that the purge time is selected from the group consisting of: a time period within a range from 1 to 4 times the void time of the GC column; and a time period within a range from 1 minute to 5 minutes, wherein the void time is the amount of time an analyte spends in a carrier gas from the time it is injected into the carrier gas to the time it reaches a detector, wherein the analyte is not retained by a stationary phase in the GC column.

12. The GC system according to claim 10, wherein the controller is configured to control the heating device so that the column temperature is reduced from the final temperature to the dwell temperature, or the column temperature is reduced from the dwell temperature to the initial temperature, or both, at a cooling rate ranging from 100°C / min to 1000°C / min.

13. The GC system according to claim 10, wherein the controller is configured to control the heating device so that the column temperature is reduced from the final temperature to the dwell temperature at a first cooling rate, the column temperature is reduced from the dwell temperature to the initial temperature at a second cooling rate, and the first cooling rate is greater than the second cooling rate.

14. The GC system of claim 10, wherein the controller is configured to: At or after the start time of maintaining the column temperature at the dwell temperature for the isothermal dwell time, the column flow rate is increased from the initial flow rate to an elevated flow rate, and the flow rate is maintained at the elevated flow rate for a flow rate hold time that spans at least a portion of the isothermal dwell time.

15. The GC system according to claim 10, comprising a cooling device configured to actively cool the GC column, wherein the controller is configured to control the cooling device to cool the GC column according to the cooling program after the sample run time.

16. The GC system according to claim 10, wherein the controller is configured to control the carrier gas source or a flow regulator between the carrier gas source and the GC column to reduce or abort the flow of carrier gas through the GC column during at least an initial portion of the cooling program.

17. A non-transitory computer-readable medium having instructions stored thereon that, when executed by a processor, control or perform the cooling of a GC column according to the method of claim 1.

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