Liquid separation mass spectrometer system

Abstract

A mass spectrometry system comprises a liquid sample separation section, such as a liquid chromatography system comprising a column 102 configured to separate a fluid sample into an output fluid flow

Description

Field of the Invention The present invention relates to systems and methods for mass spectrometry, and in particular to improvements in liquid chromatography mass spectrometry and similar techniques, such as ion chromatography, electrophoresis, and super-critical fluid chromatography. Background of the Invention Mass spectrometry is a technique by which accurate and precise ion and mass measurements can be achieved. Molecules can be analysed according to their molecular mass and their abundance within a sample. An example of a well-known mass spectrometer is the range of Orbitrap™ mass spectrometers manufactured by Thermo Fisher Scientific, Inc. The Orbitrap™ is an ion trap mass spectrometry analyser that consists of two outer electrodes and a central electrode, which enable it to act as both an analyser and detector. Ions entering a “separation” area of the Orbitrap™ are captured through "electrodynamic squeezing", after which they oscillate around the central electrode and in between the two outer electrodes. Different ions oscillate at different frequencies, resulting in their separation. By measuring the oscillation frequencies induced by ions on the outer electrodes, the mass spectra of the ions can be acquired using image current detection to highlight and identify peaks in the sample. Liquid chromatography mass spectrometry (LC-MS) combines the physical separation of components using liquid chromatography with the mass analysis provided by a mass spectrometer. Liquid chromatography (LC) separates components in a mixture, which are passed sequentially to a mass spectrometry that analyses each component. A schematic drawing of a LC-MS arrangement is shown in Figure 1. However, the LC component of a LC-MS can generate sample components more quickly than the MS component can analyse them effectively, especially for low concentration components or compounds of interest. This can lead to poor MS results. US10115577B1 discloses a gas chromatography system using a “tube or flask” to adjust the width and nature of peaks in the sample. US3916692A discloses a system in which a sample is pumped into a chromatographic column from an upstream loop. There is a need for a convenient and effective way of improving the generation of data in mass spectrometry readings. In particular, there is a need for a convenient and effective way of increasing the precision and / or efficiency of liquid chromatography mass spectrometry measurements and similar techniques. Summary of the Invention There is provided a mass spectrometry system comprising a liquid sample separation section (e.g., a liquid chromatography (LC) section or separation section), which separates a liquid sample into an output fluid flow of sample components, including target compounds. The liquid sample separation section may use one or more columns to separate a liquid sample into its component parts or sample components, which exit the one or more columns sequentially. Individual sample components are passed to a mass spectrometer (MS), which analyses the sample components separated by the liquid sample separation (e.g., LC) section. However, it has been found that the speed at which the liquid sample separation section can produce individual sample components exceeds the speed at which they can be accurately analysed by the mass spectrometer, especially for low concentration analytes. The invention seeks to increase the time duration that the sample components (especially the target compounds) can be analysed by the mass spectrometer so that they can be analysed with a required precision. This is achieved by a trapping or broadening section, which temporarily traps the sample components and extends their duration (e.g., by dilution). This can be done selectively with only sample components of interest (target compounds) being trapped. Preferably, the volume of the trapping section matches or approximates the volume of the sample component. Both extending the duration of the passage of individual sample components and matching their volume may be achieved by using a trapping section formed from a curved tube, capillary tube, looped tube, helical tube or other bent pipe or tube with an internal diameter larger than an internal diameter of the transfer capillaries. Therefore, the trapping section can be regarded as a selective peak broadening device or section. In an example implementation, a valve or valve system can selectively divert the sample components. For example, when a sample component of interest (target compound) is exiting from the separation section (e.g., LC section) then it may be diverted into the trapping section. This may be detected by an external detector (e.g., optical), for example. When sample components (e.g., a matrix component or solvent) is produced by the separation section then it may be diverted by the valve or valve system into a waste unit (e.g., drain or waste receptacle). The valve or valve system may also manage the passage of material into the MS. For example, the sample components may be directed directly to the MS bypassing the trapping section. The valve or valve system can be configured to empty the trapping section into the MS. The rate at which the trapping section is emptied into the MS can be further controlled if necessary. For example, a carrier pump (having a controllable flow rate or output pressure) can be diverted into the trapping section (for example by using the valve or valve system) so that the duration at which the sample travels past a particular point can be extended by a selectable amount, which may match to the sensitivity of the MS for a particular analyte or group of analytes. The valve or valve system may also be configured to provide a reference sample to the MS instead of the sample components. This reference sample may be provided by a further pump, such as an HPLC (High-Performance Liquid Chromatography) pump or a syringe pump, that also has a controllable speed. The type of mass spectrometer used in the invention may be a Fourier Transform (FT) mass spectrometer, such as an Orbitrap™, which is generally designed to receive “small” quantities of sample. However, by varying the concentration of the sample, even smaller and also larger quantities can be used. In this way, the system allows a user to vary the performance of the apparatus in accordance with particular requirements for different sample types. 06 05 25 Positioning a peak broadening or trapping section downstream, rather than upstream, of a chromatography section allows for peak broadening, more particularly selective peak broadening, which assists and improves the analysis of the mass 5 spectrometry signals. This is the converse or opposite of what has been suggested in the prior art, particularly US3916692A. The peak broadening or trapping section may be configured to provide selective peak broadening. For example, the ratio between the internal diameters, or relative internal 10 diameters, of the separation section and the peak broadening section may be controlled and / or adjusted to achieve improve or provide optimal peak broadening. The peak broadening or trapping section may comprise a trapping loop, for example, configured to trap a liquid fluid sample for analysis to broaden a peak of a fluid 15 sample for analysis by the mass spectrometer. The peak broadening or trapping section may comprise one, or two trapping loops, or a plurality of trapping loops (sequential or in parallel). Because of its positioning downstream, not upstream, of the separation section, the 20 trapping section may also improve mixing of a sample, which is advantageous in spectrometry in achieving the desired result. The trapping section may be in direct fluid communication with the separation section. For example, the separation section and the trapping section may be collectively 25 and / or mutually enclosed to allow or permit fluid communication between the chromatography section and the peak broadening section. For example, the separation section and the trapping section may be a part of the same fluid conduit or tube where the internal diameter of the peak broadening section is greater than the internal diameter of the separation section (which may include a narrower capillary coil, for example). For example, 30 there may be no spatial gap between the separation section and the peak broadening section but a difference in internal diameter may be formed between the two (e.g., joined by a variable diameter coupling). In accordance with a first aspect there is provided a mass spectrometry system as 35 described in claim 1. 06 05 25 The trapping section may have an internal diameter that is wider than an internal diameter of the liquid sample separation section, in particular an internal diameter that is wider than an internal diameter of capillaries, such as transfer capillaries, in the liquid 5 sample separation section. Therefore, the mass spectrometer (MS) can receive sample components separated by the liquid sample separation section (e.g., LC section) at a rate or speed that improves the precision and performance of the MS rather than receiving the sample components at 10 the same speed that they are generated by the separation section. This retains the benefits of using a combination of separation section and MS without sacrificing quality of results. The wider trapping section provides the space to achieve peak broadening whilst allowing continuous flow of a liquid through the system. This has a further benefit of increasing diffusion and mixing in an analyte of interest before being introduced into the 15 MS. The wider or thicker diameter of the trapping section (or peak broadening section) may act as a “dead volume” yet the separation section can generate sample components continuously. The trapping section is downstream of the separation section and before the MS. 20 Optionally, the trapping section may have the form of a curved tube, a helical coil, a loop, a plurality of loops, a capillary tube, or a coiled capillary tube. Other shapes may be used for the trapping section. Generally, this can be a bent or twisted tube that provides for an extended passage that that can fit within a smaller area than a straight tube. Preferably, the trapping section may take the form of a looped, coiled or helical capillary tube. This 25 trapping section can fill with a sample component slower than it is produced by or exits from the separation section. Preferably, the internal diameter of the trapping section may be two to one hundred times, preferably two to twenty times, more preferably about three to ten times wider than the internal diameter of the liquid sample separation (e.g., liquid chromatography) section (e.g., transfer capillaries). Other ratios may be used. Preferably, the tube or capillary tube of the trapping section has a circular cross-section. Optionally, the mass spectrometry system may comprise a valve arrangement configured to direct the sample components from the liquid chromatography section either to a waste receiver or to the trapping section. The valve arrangement may comprise one or move valves. The valves may be synchronised so that when sample components are directed into one section then the flow of downstream sample components or other fluids automatically flow into a different section. Optionally, the valve arrangement may be further configured to direct the slowed sample components from the trapping section either to the waste receiver or to the mass spectrometer. When the sample components are filling or flowing from the separation section into the trapping section then an output from the trapping section may be directed to the waste receiver until the trapping section is full of a particular compound of interest or peak. At this point, the valve arrangement may be switched to direct the output of the trapping section into the MS, while the output of from the separation section (that may contain only a matrix, solvent or compound that isn’t of interest) may be directed or diverted into the waste receiver or unit, or into a different detector, such as a further mass spectrometer or a CAD (charged aerosol detector). Optionally, the valve arrangement may comprise one or more valves, such as multiport valves, to be used as heart-cut valves. Other valve types may be used. Multi-port valves enable multiple different diversion of fluids to occur simultaneously and therefore provide synchronisation. One or more four-port, six-port, or seven-port valves may be used, for example. Preferably, the trapping section may be formed from glass, metal and / or plastics. Other materials may be used. Preferably, the mass spectrometer may be a Fourier transform mass spectrometer, FT-MS. Other MS types may be used. However, FT-MS work very well with LC. Preferably, the trapping section may be in direct fluid contact with the liquid chromatography section. The interface between the separation section and the trapping section may be fluid-tight and sealed or joined by one or more valves. Optionally, the trapping section may have a mixing spindle. This can be used to improve mixing and further slow or broaden the LC peak. Optionally, the mass spectrometry system may further comprise a first supply pump (e.g., an eluent pump) configured to and / or positioned to provide a sample or an eluent, to the liquid chromatography section. This first pump can drive the separation section, which in turn pumps the sample components separated by the separation section into the trapping section (or to waste when an unwanted component is emitted). Optionally, the mass spectrometry system may further comprise a carrier (second) pump, that is configured to and / or positioned to provide a carrier fluid to the trapping section. The carrier pump can be configured to pump into the trapping section (e.g., containing a compound of interest forming a sample component) and out into the MS. Preferably, the carrier pump may have a variable speed and may be configured to vary the passage of the sample components from the trapping section and into the mass spectrometer. Therefore, the speed or rate at which the MS receives and analyses the sample components can be further varied (in addition to the being varied by the trapping section dimensions). This can be useful in optimising the analysis of different compounds that may require different rates or concentrations by the MS. Preferably, the mass spectrometry system may further comprise a waste unit. This can be used to receive unwanted sample components, fluid used to flush or clean different components of the mass spectrometer system or maintain a constant flow of liquid within the mass spectrometry system without requiring the MS to process every fluid or component. For example, flushing may be carried out with methanol or another suitable solvent. Optionally, the mass spectrometry system may further comprise reservoir and reservoir pump configured to flush any or all passages of the mass spectrometer system. The reservoir and reservoir pump may also provide a reference sample to the MS. Optionally, the mass spectrometry system may further comprise one or more supply pumps. Optionally, the mass spectrometry system may further comprise a controller configured to control the passage of the sample components from the liquid chromatography section, in and out of the trapping section and into the mass spectrometer. The controller may be an electronic circuit or computer processor, for example. Optionally, the controller may be further configured to vary the speed at which the sample components flow from the liquid chromatography section, in and out of the trapping section and into the mass spectrometer. The controller may be formed as at least a part of a computer system. A computer program may be used within the computer system and comprise program instructions to operate the computer system. The computer program may be stored on a computer-readable medium, including a non-transitory computer-readable medium. The computer system may include a processor or processors (e.g., local, virtual or cloud-based) such as a Central Processing Unit (CPU), and / or a single or a collection of Graphics Processing Units (GPUs). The processor may execute logic in the form of a software program. The computer system may include a memory including volatile and nonvolatile storage medium. A computer-readable medium (CRM) may be included to store the logic or program instructions. For example, embodiments may include a non-transitory computer-readable medium (CRM) storing software comprising instructions executable by one or more computers which, upon such execution, cause the one or more computers to perform the disclosed methods. Non-transitory CRM may refer to a CRM that stores data for short periods or in the presence of power such as a memory device or Random Access Memory (RAM). For example, a non-transitory computer-readable medium may include storage components, such as, a hard disk (e.g., a magnetic disk, an optical disk, a magneto-optic disk, and / or a solid state disk), a compact disc (CD), a digital versatile disc (DVD), a floppy disk, a cartridge, and / or a magnetic tape. The different parts of the system may be connected using a network (e.g. wireless networks and wired networks). The 06 05 25 computer system may include one or more interfaces. The computer system may contain a suitable operating system such as UNIX, Windows (RTM) or Linux, for example. According to a further aspect, there is provided a method for operating a mass 5 spectrometer system, as described in claim 20. The method may use the any of the mass spectrometer systems described above. The method may further comprise using the mass spectrometer to carry out an isotope ratio analysis, which may allow a high-end quantisation of ion signals. 10 It should be noted that any feature described above may be used with any particular aspect or embodiment of the invention. Brief description of the Figures 15 The present invention may be put into practice in a number of ways and embodiments will now be described by way of example only and with reference to the accompanying drawings, in which: Fig. 1 shows a schematic diagram of a conventional system for mass spectrometry, according to the prior art; 20 Fig. 2 shows a schematic diagram of a mass spectrometry system, including a separation section, according to the described systems and methods; Fig. 3 shows a schematic diagram of a further mass spectrometry system, including a separation section, according to systems and methods of the present invention; Fig. 4 shows a schematic diagram of a further mass spectrometry system according 25 to systems and methods of the present invention; Fig. 5 shows a graph of intermediate results obtained using the described systems and methods; Fig. 6 shows a graph of further intermediate results obtained using the described systems and methods; Fig. 7 shows a table of results obtained using the described mass spectrometry system compared with a prior art mass spectrometry system, together with chemical formulas of the sample analytes; Fig. 8 shows a schematic diagram of a computer system used to control the mass spectrometry system of figures 2, 3, 4 and 5; Fig. 9 shows a schematic diagram illustrating peak broadening within a trapping section of the mass spectrometry system of figures 2, 3, 4 and 5; and Fig. 10 shows a schematic diagram of an example separation section of figure 2 and figure 3. It should be noted that the figures are illustrated for simplicity and are not necessarily drawn to scale. Like features are provided with the same reference numerals. Detailed description of the preferred embodiments As mentioned above, Figure 1 shows a schematic diagram of a mass spectrometry system 10 known in the art. The system comprises a first supply pump or high performance liquid chromatography (HPLC) pump 12, such as an eluent pump, for supplying a sample, such as an eluent, to a liquid separation column 14, such as a liquid chromatography (LC) section or chromatography column. From there, the sample is provided to a mass spectrometer (MS) 16 in which mass spectrometry is performed to analyse the sample. In direct contrast, Figure 2 shows a mass spectrometry system 100 according to an example implementation. In this example implementation, the liquid sample separation section is a liquid chromatography section, which may comprise a chromatographic column. In some embodiments, the liquid sample separation section may comprise another sample separation component, such as an electrophoresis capillary. The mass spectrometry system 100 comprises a pump 101, such as an HPLC (High-Performance Liquid Chromatography) pump, the liquid chromatography (LC) section or liquid sample separation section (separation section) 102 configured to receive a fluid sample for analysis, a trapping section or peak broadening section (or a peak broadening portion or conduit) 104 in fluid communication with the separation section 102, and a mass spectrometer (MS) 106 in fluid communication with the trapping section 104. For example, the sample separation section 102 may comprise a column (or a separation element) having capillaries leading to and from the column. The internal diameter of the column may be larger than the internal diameters of these capillaries. The column may be filled with an adsorbent material. In an example implementation, the column may have a relatively large inner diameter, even larger than the inner diameter of the trapping section. The column may be prepared by packing a solid adsorbent into a cylindrical glass or plastic tube. The type of MS used in any embodiment of the invention may be a Fourier Transform (FT) mass spectrometer (FT-MS), such as an Orbitrap™, which is generally designed to receive small quantities of sample for analysis. However, by varying the concentration of the sample, different sized quantities can also be used. The system allows a user to adjust performance and flow rates in accordance with given aims and requirements or a particular investigation. Of course, other models or MS types may be used. In the embodiment shown in Figure 2, the mass spectrometry system 100 comprises a first supply pump 101, such as an eluent pump, that is configured and / or positioned to provide or supply a sample, such as an eluent, to the mass spectrometry system 100. However, it will be understood that any suitable sample source could easily be used (e.g., a jet or hose). In particular, the first supply pump 101 is configured and / or positioned to provide or supply a sample to the separation section 102 of the mass spectrometry 106. As shown in Figure 2 the trapping section 104 is positioned downstream of the separation section 102. In other words, the separation section 102 and the trapping section 104 are configured and / or positioned so that a sample passes through the separation section 102 before passing into a through the trapping section 104. The present inventors have realised that positioning a trapping section, or “peak broadening section” or “trapping loop” downstream, rather than upstream, of the separation section (in particular) can be a convenient way of achieving improved peak broadening, which can assist with mass spectrometry analysis. As shown in Figure 2, the trapping section 104 has an internal diameter that is wider than an internal diameter of the separation section 102 (e.g., in the form of a separation column or capillary tube). The trapping section 104 is configured to trap a liquid fluid sample in the form of sample components or compounds of interest, divided by the separation section or separation column to broaden a peak of a fluid sample for analysis by the MS 106. A single, two, or a plurality of trapping loops may be used as desired. All of these considerations also apply to the further example implementations shown in Figures 3 to 5, described below. The trapping section 104 of the system 100 shown in Figure 2 also improves the mixing of a sample, which is desirable in mass spectrometry. As shown in Figure 2, the trapping section 104 has an internal diameter (ID1) that is wider than the internal diameter (ID2) of the capillaries leading to and from the separation or LC section 102, and so allows for peak broadening and more specifically, selective peak broadening. For example, the ratio between the internal diameters of the separation section and the trapping section may be controlled and / or adjusted to achieve ideal peak broadening or slowing of the passage of a sample component through the mass spectrometer system. This is in direct contrast to known systems, including that shown in Figure 1. These benefits are also demonstrated by the arrangements shown in Figures 3 to 5, as described below. In example implementations, ID1 may be at or about 500pm and ID2 may be at or about 75pm. ID3 is the internal diameter of a capillary that provides the sample liquid to the MS. ID3 may be at or about 60pm. Figures 3 and 4 show systems 200 and 300, respectively, that describe ways of structuring the various components included in Figure 2 along with additional components, linkages and interfaces that can be implemented to improve its flexibility, effectiveness and utility. In particular, the various linkages, valves, pumps and interface between components allow for switching and control of the system. Similar components have the same reference numerals. Figure 3 shows a schematic diagram of the system 200, which comprises a separation section (or a chromatography portion or chromatography conduit) 102 configured to receive a fluid sample for analysis, a trapping section (or a peak broadening portion or conduit) 104 in fluid communication with the chromatography section 102, and a mass spectrometer 106 in fluid communication with the trapping section 104. A waste unit 103 can receive and dispose of carrier fluid and any sample components that do not need to be analysed by the MS 106. As with the other figures and example implementations, a first supply pump 101 is shown in Figure 3, which is configured to supply fluid (a liquid input) to the separation section 102, although other suitable sources can be used. The mass spectrometer system 200 comprises a valve 210, that is connected between the separation section 102 and other parts. The valve 210 is also fluidly coupled via at least one first linkage or interface to the trapping section 104. This allows for the switching or selecting of peak broadening to occur (or be absent) within the system 200. The valve 210, in this example implementation, has six ports (a-f). The value 210 may be a heart-cut valve where neighbouring ports can be selectively connected (i.e., fluidly connected) or disconnected. For example, in a first configuration, the connected ports may be a-b, c-d, and e-f. Therefore, the first supply pump 101 drives a sample fluid through the separation section 102, into valve port a, out of valve port b, into the trapping section 104. Any previous sample components already within the trapping section are driven out of the trapping section 104, into valve port e, out of valve port f and into the waste unit 103. Therefore, the trapping section 104 can fill at one end with a sample component containing a compound of interest while empty at its other end of fluid or other sample components that do not require analysis. The fluid flow speed, width and viscosity of the sample may be selected to limit or eliminate any substantial mixing of sample components within the trapping section 104. The valve 210 can switch (e.g., manually or by a controller that is not shown in this figure) so that a different combination of neighbouring ports are connected. In this second configuration the connected ports may be c-b, e-d, and a-f. Therefore, in this second configuration, an output from the separation section 102 (e.g., one containing a sample component or solvent that doesn’t require analysis) is diverted directly to the waste unit 103. A second supply pump 220 drives carrier fluid into valve port c, out of valve port b and into the trapping section 104, which had been previously filled with a sample component containing a compound of interest when the valve 210 was in the first valve configuration. The sample component within the trapping section 104 is driven out of the trapping section, into valve port e, out of valve port d and into the MS 106. The speed or rate at which the MS 106 can receive the sample component can be determined both by the slowing effect of the trapping section 104 (e.g., due to its length, volume and diameter) and by the speed of the second supply pump 220. This pump speed may be controlled by a controller (not shown in this figure) and may be tuned, set, or selected based on the type of compound, carrier fluid type, and its concentration. This can be set to match the performance of the MS 106 so that improved or optimum MS results can be obtained regardless of the speed at which the separation section 102 separates and provides a sample (peak). The system 200 of Figure 3 has sections with internal diameters similar to those of the system 100 of Figure 1. ID4 illustrates an internal diameter of an output from the supply pump 220. In an example implementation, this internal diameter may be about 20pm. Figure 4 shows a schematic diagram of a further example implementation. Similar components have the same reference numerals. The system 300 shown in Figure 4 provides additional functionality. In particular, this system 300 enables a reference sample to be selectively provided to the MS 106. A reference sample may be supplied by a reference reservoir and pump 310. This allows calibration and optimisation of the MS 106 so that improved results can be achieved when analysis of a compound of interest is carried out. A second valve 320 (B) is included in addition to the first valve 210 (A) described with reference to Figure 3. The second valve 320 may be operated and controlled independently or in synchronisation with the first valve 210. Again, a controller 330 may control and coordinate any one or more of the valves, pumps, MS 106 in this MS system 300. Figure 4 illustrates the first valve 210 in its first configuration (b-c, d-e, and f-a). In this figure, double lines indicate connection of ports. The waste unit 103 and trapping section 104 are connected to different valve ports of the first valve 210. However, in this first valve 210 configuration, the output from the separation section 102 is still diverted to the waste unity 103 directly through valve 210 ports b and c. The second pump 220 (carrier pump in Figure 4) provides carrier fluid to the trapping section 104 through valve 210 ports f and out of a. The second valve 320 is in its first port configuration with ports connected as A-F, B-C (no flow), and D-E (diverting reference sample fluid to the waste unit 103 if flushing is required). Therefore, with both valves (210, 320) in their first valve port configurations, the trapping section 104 is emptied by the second pump 220 into the MS 106 through valve 320 ports A and F. With both valves switched to their second configuration, the valve ports are as follows. First valve 210: a-b, c-d, and e-f. Second valve 320: A-B, C-D, and E-F. This connects an output of the separation section 210 to the trapping section 104 (through valve ports a and b), connects the output of the trapping section 104 to the waste unit 103 through valve 210 ports c and d (so that an unwanted sample component is not analysed by the MS 106). The second pump 220 is connected to the waste unit 103 through valve 320 ports A and B (e.g., to flush to valve 320) and the reference reservoir and pump 310 is connected through valve 320 ports E and F to the mass spectrometer so that a reference sample can be analysed, if necessary. If a reference sample is not required to be analysed by the MS 106, then the reference pump does not operate. This may be controlled by the controller 330, preferably a computer controller. Therefore, by switching valve 210 (A) when a target compound is eluting from the separation section 102, the liquid containing the analyte of interest can be trapped inside the trapping section 104. In this arrangement, the trapped and broadened peak can either be directly eluted with the first (eluent) pump 101 or with the second (carrier) pump 220, with the controller 330 managing the pump speed of the second pump 220 to achieve different levels of peak broadening or slowing. The first pump 101 may be maintained by the controller 330 at an optimum or preferred flow rate to operate the separation section 102. As shown in Figures 2 to 4, in these example implementations the separation section 102 contains one or more capillaries with a diameter of 75 pm. The width of the trapping section 104 is 500 pm in this example. This ratio is 6.7 but other values and ratios may be used (e.g., 2, 3, 4, 5, 6, 7, 8, 9, and 10). However, improved results are apparent when a ratio of at least around 3 to 5 is used. The length of the capillary forming the trapping section may be several cm (e.g., 3-5cm). The shape may take the form of a helix, coil, loop, twist, zig-zag or other suitable shape. Bends within the trapping section can further slow the passage of fluid and so increase peak broadening. Furthermore, this can improve mixing within a sample component. The interface with the MS 106 (e.g., from one or more of the valves or directly from the trapping section 104) may take the form of a 60 pm capillary, for example. Figure 5 shows a graph 400, illustrating peak widths when using the trapping section (loop) 104 compared to when the trapping section 104 is not used (i.e., using the system 10 of Figure 1). The y-axis of graph 400 is in arbitrary units (a.u.) with the x-axis in minutes. This graph illustrates results from a caffeine sample passing through a reversed phase LC. The sample is then passed into the MS 106 but these results are not shown in this graph. The full width, half maximum (FWHM) of the peak without the use of the trapping section 104 is 0.0666 minutes and 0.4643 minutes with the use of the trapping section 104 (approximately a 7-times increase). These results were obtained without the use of the second (carrier) pump 220 and rely on the first (eluent) pump 101 only (i.e., operating according to the requirements of the separation section 102). Figure 6 shows a further graph 500 of a similar sample (caffeine) passing through the same separation section 102 and trapping section 104. However, in this graph 500 the LC peak is further broadened by slowing the flow rate using the second (carrier) pump 220 to apply slowed fluid to the trapping section 104 (instead of the eluent pump speed). These results show the peak can be further broadened to at least 12.5 minutes or a 27-times increase over the usual (non-broadened) LC peak for the sample. The section marked A in Figure 6 shows the passing of a reference sample (block 1). The section marked B in Figure 6 shows a broadened sample peak. The section marked C in Figure 6 shows the passing of another reference sample (block 2). Figure 7 shows a table 600 of results illustrating an improvement of MS performance for the combined broadening performed by the system 300 shown in Figure 4. The precision of a 13C and 15N isotopologue ratio analysis (molecular structures differing only in their isotopic composition) of caffeine in six different drinks, shows an improvement using the described systems and methods. The average standard error for both analyses reduced significantly when broadened LC peaks entering the MS 106 when compared to LC coupling without any broadening. Figure 7 also shows the chemical formula of the example analyte (caffeine - C8H11N4O2), which is analysed as [M + H]+. The analysed isotope ratios are also shown. In the table of Figure 7, the left column results are average standard error by a mean of five sample injections for 513Cvpdb[%o] and the right column results are average standard error by a mean of five sample injections for b15NAir[%o] In these specific example tests, simultaneous, multiple higher precision isotopologue ratios can be obtained from intact compounds in complex mixtures utilising on-line HPLC coupling to atmospheric pressure ionisation MS instruments. These improvements are also seen with different samples and MS types. Samples of very high to very low concentrations may be used with the systems described above. This can be strongly dependent on analyte type. In an example set of tests 1 nmol of analyte has been investigated. The controller 330 may be implemented as a computer system electrically interfacing with the components described with respect to any of the figures. The interfaces may be switches (e.g., for the values) or speed controllers (e.g., for the pumps). As shown in Figure 8, the computer system 800 includes a number of components including communication interfaces 820, system circuitry 830, input / output (I / O) circuitry 840, display circuitry and interfaces 850, and a datastore 870. The system circuitry 820 can include one or more processors or CPUs 880 and memory 890. The system circuitry 830 may include any combination of hardware, software, firmware, and / or other circuitry. The system circuitry 830 may be implemented, with one or more systems on a chip (SoC), application specific integrated circuits (ASIC), microprocessors, and / or analogue and digital circuits. The display circuitry may provide one or more graphical user interfaces (GUIs) 860 and the I / O interface circuitry 840 may include touch sensitive or non-touch displays, sound, voice or other recognition inputs, buttons, switches, speakers, sounders, and other user interface elements. The I / O interface circuitry 840 may include microphones, cameras, headset and microphone input / output connectors, Universal Serial Bus (USB) connectors, and SD or other memory card sockets. The I / O interface circuitry 840 may further include data media interfaces (e.g., a CD-ROM or DVD drive) and other bus and display interfaces. The memory 890 may include volatile (RAM) or non-volatile memory (e.g., ROM or Flash memory). The memory may store the operating system 892 of the computer system 800, applications or software 894, dynamic data 896, and / or static data 898. The datastore or data source 870 may include one or more databases 872, 874 and / or a file store or file system, for example. Figure 9 shows a schematic diagram illustrating how sample components may be stretched or elongated by dilution as they pass through the trapping section 104. It will be clear from Figure 9 that D1 «D3 and that D2>D1, where D2 is the diameter of the trapping section 104 and D1 and D3 are the diameters of capillaries leading to and from the trapping section respectively. It should be noted that the fluid velocity vi«v2 if Di«D2. The sample component is shown without broadening as 910 and after broadening as 920 with L2>L1. The diagram is not to scale as the capillaries may be around 100cm in length either side of an approximately 10cm long trapping section (which may also be wider than shown in this figure). Furthermore, the sample components may not have the sharp boundaries as shown in this figure. Instead, the sample concentration may vary as a function of time at a certain point, which may take the form of a Gaussian curve. This may be important to consider during operation when the sample component is “cut out” using the one or more valve. Figure 10 shows a schematic diagram of an example separation section 102 in more detail. The separation section includes a separation element (e.g., column) 1010 and a first capillary 1020 that leads into the separation element 1010 and a second capillary 1030 that leads out of the separation element 1010. The inner diameter (ID2) of the first and second capillaries may be narrower than that of the inner diameter (ID1) of the trapping section or broadening device 104. In an example implementation, a chromatographic column may act as the separation section or element 1010 with the chromatographic column containing a solid substance (an adsorbent) and the trapping section being substantially empty. Such a chromatographic column may take the form of a cylindrical glass or plastic tube packed with a solid adsorbent. A base of the column may contain a filter, such as a cotton or glass wool plug, for example. Furthermore, an inner diameter of the chromatographic column may have an inner diameter that is wider than the trapping or broadening section. The trapping or broadening section should have a wider inner diameter than capillaries leading to and from the chromatographic column (whatever its relative inner diameter) or a similar component, such as an electrophoresis capillary. As used throughout, including in the claims, unless the context indicates otherwise, singular forms of the terms herein are to be construed as including the plural form and vice versa. For instance, unless the context indicates otherwise, a singular reference herein including in the claims, such as "a" or "an" (such as an ion multipole device) means "one or more" (for instance, one or more ion multipole device). Throughout the description and claims of this disclosure, the words "comprise", "including", "having" and "contain" and variations of the words, for example "comprising" and "comprises" or similar, mean "including but not limited to", and are not intended to (and do not) exclude other components. Also, the use of “or” is inclusive, such that the phrase “A or B” is true when “A” is true, “B is true”, or both “A” and “B” are true. The use of any and all examples, or exemplary language ("for instance", "such as", "for example" and like language) provided herein, is intended merely to better illustrate the disclosure and does not indicate a limitation on the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure. The terms “first” and “second” may be reversed without changing the scope of the disclosure. That is, an element termed a “first” element may instead be termed a “second” element and an element termed a “second” element may instead be considered a “first” element. Any steps described in this specification may be performed in any order or simultaneously unless stated or the context requires otherwise. Moreover, where a step is described as being performed after a step, this does not preclude intervening steps being performed. It is also to be understood that, for any given component or embodiment described throughout, any of the possible candidates or alternatives listed for that component may generally be used individually or in combination with one another, unless implicitly or explicitly understood or stated otherwise. It will be understood that any list of such candidates or alternatives is merely illustrative, not limiting, unless implicitly or explicitly understood or stated otherwise. Unless otherwise described, all technical and scientific terms used throughout have a meaning as is commonly understood by one of ordinary skill in the art to which the various embodiments described herein belongs. As will be appreciated by the skilled person, details of the above embodiment may be varied without departing from the scope of the present invention, as defined by the appended claims. For example, different types of liquid chromatography sections may be used as well as different types of mass spectrometers. For example, isotope ratio mass spectrometers (IRMS), time-of-flight (TOF) mass spectrometers, triple quad mass spectrometers, Fourier transform - ion cyclotron resonance (FT- ICR) mass spectrometers and mass spectrometers such as the Thermo Scientific™ Astral™. Different diameter tubes or pipes may be used with the trapping or broadening section. The system may be used with many different analytes (e.g., vanillin, amino acids, short chain fatty acids, etc.). The trapping section may also include or take the form of a flask or beaker. Many combinations, modifications, or alterations to the features of the above embodiments will be readily apparent to the skilled person and are intended to form part of the invention. Any of the features described specifically relating to one embodiment or example may be used in any other embodiment by making the appropriate changes. 06 05 25

Claims

1. A mass spectrometry system comprising:a liquid chromatography section configured to separate a fluid sample into an output 5 fluid flow of sample components;a mass spectrometer configured to analyse the sample components separated by the liquid chromatography section; anda trapping section configured to receive the output fluid flow of sample components from the liquid chromatography section and to provide the sample components to the mass 10 spectrometer so as to extend the time that the sample components are analysed in the mass spectrometer, wherein the trapping section has the form of a helical coil.

2. The mass spectrometer system of claim 1, wherein the trapping section has an internal diameter that is wider than an internal diameter of capillaries of the liquid15 chromatography section.

3. The mass spectrometry system of claim 1 or claim 2, wherein the internal diameter of the trapping section is two to one hundred times wider than the internal diameter of the liquid chromatography section.

204. The mass spectrometry system of claim 1 or claim 2, wherein the internal diameter of the trapping section is two to twenty times wider.

5. The mass spectrometry system of claim 1 or claim 2, wherein the internal diameter 25 of the trapping section is three to ten times wider.

6. The mass spectrometry system according to any previous claim further comprising a valve arrangement configured to direct the sample components from the liquid chromatography section either to a waste receiver or to the trapping section.

307. The mass spectrometer system of claim 6, wherein the valve arrangement is further configured to direct the slowed sample components from the trapping section either to the waste receiver or to the mass spectrometer.06 05 258. The mass spectrometry system of claim 6 or claim 7, wherein the valve arrangement comprises one or more heart-cut valves.

9. The mass spectrometry system according to any previous claim, wherein the 5 trapping section is formed from glass, metal and / or plastics.

10. The mass spectrometry system according to any previous claim, wherein the mass spectrometer is a Fourier transform mass spectrometer.10 11. The mass spectrometry system according to any previous claim, wherein thetrapping section is in direct fluid contact with the liquid chromatography section.

12. The mass spectrometry system according to any previous claim, further comprising a first supply pump configured to and / or positioned to provide a sample or an eluent, to the 15 liquid chromatography section.

13. The mass spectrometry system according to any previous claim, further comprising a carrier pump, that is configured to and / or positioned to provide a carrier fluid to the trapping section.2014. The mass spectrometry system of claim 13, wherein the carrier pump has a variable speed and is configured to vary the passage of the sample components from the trapping section and into the mass spectrometer.25 15. The mass spectrometry system according to any previous claim further comprisinga waste unit.

16. The mass spectrometry system according to any previous claim further comprising reservoir and reservoir pump configured to flush any or all passages of the mass30 spectrometer system.

17. The mass spectrometry system according to any previous claim further comprising one or more supply pumps.06 05 2518. The mass spectrometry system according to any previous claim further comprising a controller configured to control the passage of the sample components from the liquid chromatography section, in and out of the trapping section and into the mass spectrometer.5 19. The mass spectrometry system of any one of the preceding claims, wherein thecontroller is further configured to vary the speed at which the sample components flow from the liquid chromatography section, in and out of the trapping section and into the mass spectrometer.10 20. A method for operating a mass spectrometer system comprising the steps of:separating a fluid sample into an output fluid flow of sample components using a liquid chromatography section;analysing the sample components separated by the liquid chromatography section using a mass spectrometer; and15 extending the time that the sample components are analysed in the massspectrometer using a trapping section having the form of a helical coil configured to receive the output fluid flow of sample components from the liquid chromatography section and provide the sample components to the mass spectrometer.20 21. The method according to claim 20, further comprising using the mass spectrometerto carry out an isotope ratio analysis.

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