Interfacing capillary electrophoresis to a mass spectrometer via an impactor spray ionization source

Cross-reference of related applications

This application is filed in US Provisional Patent Application Serial No. 61/580558 (Filing Date: December 27, 2011), US Provisional Patent Application Serial No. 61/601827 (Filing Date: February 22, 2012), US Provisional Patent Application Serial No. 61/7183836 (Filing Date: October 26, 2012), UK Patent Application No. 1122218.9 (Filing Date: December 23, 2011), UK Patent Application No. 1202892.4 (Filing Date) : February 21, 2012), and claims priorities and benefits from UK Patent Application No. 1219217.5 (Filing Date: October 25, 2012). The entire contents of these applications are incorporated herein by reference.

Capillary electrophoresis (CE) is a separation technique in which a high voltage is applied to the sample inlet end of a glass capillary column and a lower voltage or voltage of different polarity is applied to the outlet end of the capillary. The analyte elutes from the column at a rate determined by the combination of electroosmotic flow and electrophoresis mobility of the analyte. Since the electroosmotic flow rate may exceed the ion electrophoresis drift rate, it is possible to analyze both positive and negative ions in the same chromatograph separation. In such a situation, if the elution order is ruled, first polyvalent positive ions are generated, then monovalent positive ions are generated, then a neutral analyte is generated, then monovalent negative ions are generated, and finally. Multivalent negative ions are generated in. Commonly used CE detectors (eg, UV and fluorographs) can analyze the ionic polarities of both in a single chromatograph run.

However, when interfaced CE to mass spectrometry via an electron spray ionization source, the column outlet is located at the tip of the electron spray probe, which is then via a separate high voltage source and voltage divider circuit. Typically 3kV is biased. In order to analyze positive and negative ions, it is necessary to set the ESI tip voltage to + 3kV and -3kV, respectively. As a result, the overall CE voltage and thus the electroosmotic and electrophoretic flows are affected, making it impossible to use positive / negative switching at high speed in a single chromatograph run.

Another disadvantage of traditional layout configurations is that biasing the ESI tip requires additional cost for the ESI power supply circuit. In addition, such an arrangement limits buffer concentration and ESI voltage stability.

Therefore, it is desired to provide an improved mass spectrometer.

According to aspects of the invention, a mass spectrometer is provided that includes: A separator configured and adapted to release the eluent over time, the separators being: (i) a capillary electrophoresis (CE) separator, (ii) a capillary electron chromatography (ii) Separation, including either (CEC)) separator, (iii) a substantially rigid ceramic-based multilayer microfluidic substrate (ceramic tile) separator, or (iv) supercritical fluid chromatography separator. With the device With a sprayer With the target including.

In use, the eluent released from the separator is sprayed from the atomizer and the flow of the analyte droplets is directed to collide with the target, thereby ionizing the analyte and multiple analytes. Form ions.

The present invention sprays the arrangement of a capillary electrophoresis (CE) separator and other types of separators after releasing the eluent and sprays the resulting flow of droplets upon target collision. It is particularly advantageous in that it can be arranged so as to be ionized in. Since the conventional teaching content is the interface between the CE separator and the electron spray ionization source, it is particularly advantageous when the CE separator is interfaced so as to collide with the ionization source according to the present invention. However, in that case, in order to generate negative ions, it is necessary to maintain the tip of the electron spray probe at + 3kV and to be able to quickly switch the tip of the probe to -3kV. When connected to a CE separator, it is difficult to maintain the electron spray probe tip at 3 kV, and rapid switching of the probe tip voltage can affect the overall CE voltage, resulting in electricity. This is not possible because it also affects the permeation and electrophoresis flow.

Therefore, according to the present invention, the probe tip can be maintained at, for example, a ground potential, avoiding the costs and complications associated with high-speed switching high-voltage power supply for the probe.

In the present invention, since the CE separator is connected to the collision ionization source, it is particularly advantageous as compared with the conventional arrangement configuration in which the CE separator interfaces with the high voltage electron spray ionization source.

According to a preferred embodiment of the invention, the liquid flow from the outlet of the capillary electrophoresis column is connected to the inner capillary of the grounded triaxial pneumatic atomizer probe. A stream of constituent solutions is added to the second concentric capillary. The second concentric capillary mixes the flow from the inner capillary at the probe tip. The resulting liquid flow is converted to a spray spray via a high speed concentric flow from the third concentric capillary. By preferably placing the small impactor target relatively close to the tip of the atomizer, a collision zone is defined and the incoming high speed droplet flow is ionized. The resulting vacuum-stage mass spectrometer samples the resulting ions and charged droplets.

The ionized high voltage is separated from the probe tip, allowing the grounded probe assembly to be used advantageously. This grounded probe assembly serves as a stable reference for the applied CE voltage. This is particularly advantageous as compared to the conventional arrangement configuration.

The nebulizer probe tip is preferably held at the ground potential (or relatively close to it) and any high voltage for ionization is preferably held on the impactor target. The impactor target is placed at a short distance from the tip. This configuration eliminates the above problems and allows both positive and negative ions to be analyzed in a single CE / MS run using fast polarity switching of the impactor target.

The impactor spray source can generally operate at a liquid flow 1 μL / min. However, because the electroosmotic flow associated with the CE column is extremely low (<< 1 μL / min), the impactor spray atomizer probe is preferably constructed with a 3-axis probe configuration that increases the overall liquid flow rate. The inner capillary is preferably connected to the outlet of the CE capillary column. The inner capillaries are preferably surrounded by a second concentric capillary. The second concentric capillary preferably delivers a constituent flow of liquid mixed with the liquid flow from the CE column. The second capillary is preferably surrounded by a third concentric capillary. The third concentric capillary preferably delivers high speed nitrogen gas and sprays the resulting liquid flow through two other capillaries. It is preferable to keep all three capillaries in the three-shaft arrangement configuration at ground potential. The impactor target is preferably held at a relatively high potential and is preferably placed relatively close to the probe tip.

According to a preferred embodiment, the liquid flow from the outlet of the capillary electrophoresis column is connected to the inner capillary of a grounded, preferably triaxial pneumatic atomizer probe. A stream of constituent solutions is added to the second concentric capillary. The second concentric capillary mixes with the flow of the inner capillary at the probe tip. The resulting liquid flow is converted to a spray spray via a high speed concentric flow from the third concentric capillary. The small impactor target is placed very close to the tip of the atomizer, defining a collision zone and ionizing the incoming high speed droplet flow. The resulting ions and charged droplets are sampled by the first vacuum step of the mass spectrometer.

In a preferred embodiment, the interface problem is alleviated by using a grounded probe assembly that cuts from the ionized high voltage probe tip and preferably serves as a stable reference for the applied CE voltage. In impactor spray ionization, the atomizer probe tip is preferably held at ground potential and any high voltage for ionization is preferably held on the impactor target. The impactor target is preferably placed at a short tip distance. This configuration solves the above problems and also allows both positive and negative ions to be analyzed in a single CE / MS run using impactor target fast polarity switching.

For high voltage ESI atomizer probes, interfacing MS sources with high voltage chromatography techniques (eg CE and CEC) can be complicated. A preferred embodiment solves the problem of generating ionizations without applying a high voltage directly to the atomizer probe.

The separator preferably includes a capillary electrophoresis (CE) separator. The inlet end of the capillary electrophoresis separator is maintained at the first potential and the outlet end of the capillary electrophoresis separator is maintained at the second potential.

The separator preferably comprises or is connected to a first tube.

The first tube preferably comprises a capillary tube.

The outlet of the first tube is preferably maintained at the following potentials during use: (i) -5 ~ -4kV; (ii) -4 ~ -3kV; (iii) -3 ~ -2kV; (iv) -2 ~ -1kV; (v) -1000 ~ -900V; (vi) -900 ~ -800V; (vii) -800 ~ -700V; (viii) -700 ~ -600V; (ix) -600 ~ -500V; (x) -500 ~ -400V; (xi) -400 ~ -300V; (xii) -300 ~ -200V; (xiii) -200 ~ -100V; (xiv) -100 ~ -90V; ( xv) -90 ~ -80V; (xvi) -80 ~ -70V; (xvii) -70 ~ -60V; (xviii) -60 ~ -50V; (xix) -50 ~ -40V; (xx) -40 ~ -30V; (xxi) -30 ~ -20V; (xxii) -20 ~ -10V; (xxiii) -10 ~ 0V; (xxiv) 0 ~ 10V; (xxv) 10 ~ 20V; (xxvi) 20 ~ 30V; (xxvii) 30 ~ 40V; (xxviii) 40 ~ 50V; (xxix) 50 ~ 60V; (xxx) 60 ~ 70V; (xxxi) 70 ~ 80V; (xxxii) 80 ~ 90V; (xxxiii) 90 ~ 100V; ( xxxiv) 100 ~ 200V; (xxxv) 200 ~ 300V; (xxxvi) 300 ~ 400V; (xxxvii) 400 ~ 500V; (xxxviii) 500 ~ 600V; (xxxix) 600 ~ 700V; (xl) 700 ~ 800V; (xli) ) 800 ~ 900V; (xlii) 900 ~ 1000V; (xliii) 1-2kV; (xliv) 2-3kV; (xlv) 3 ~ 4kV; and (xlvi) 4 ~ 5kV.

According to less preferred embodiments, the outlet of the first tube can be maintained at a potential of <-5 kV or> 5 kV.

The first tube is preferably surrounded by the second tube. The second tube is arranged and adapted to provide a liquid flow that mixes with the eluate exiting the outlet of the first tube.

The second tube preferably comprises a capillary tube.

The ends of the first and second tubes are (i) coplanar or parallel to each other, or (ii) projecting, concave or non-parallel to each other. is there.

The mass spectrometer preferably includes a third tube. The third tubing may surround the second tubing and is arranged and adapted to provide gas flow to the outlet of the first tubing and / or the second tubing.

The third tube preferably includes a capillary tube.

The third tube preferably surrounds the second tube and / or is concentric with the first and second tubes.

According to embodiments, the ends of the first, second and third tubes can (i) be coplanar or parallel to each other, or (ii) mutually. Protruding, concave or non-parallel.

According to another embodiment, the third tube can be non-concentric with the first and second tubes.

The mass spectrometer preferably further includes a heater. The heater is arranged and adapted to supply a heated gas stream to heat the droplets emitted from the first and / or second tube.

Targets are preferably configured to be <10 mm, <9 mm, <8 mm, <7 mm, <6 mm, <5 mm, <4 mm, <3 mm or <2 mm from the outlet of the atomizer.

The target is preferably maintained at the following potentials during use: (i) -5 ~ -4kV; (ii) -4 ~ -3kV; (iii) -3 ~ -2kV; (iv) -2 ~ -1kV; (v) -1000 ~ -900V; (vi) -900 ~ -800V; (vii) -800 ~ -700V; (viii) -700 ~ -600V; (ix) -600 ~ -500V; ( x) -500 ~ -400V; (xi) -400 ~ -300V; (xii) -300 ~ -200V; (xiii) -200 ~ -100V; (xiv) -100 ~ -90V; (xv) -90 ~ -80V; (xvi) -80 ~ -70V; (xvii) -70 ~ -60V; (xviii) -60 ~ -50V; (xix) -50 ~ -40V; (xx) -40 ~ -30V; (xxi) ) -30 ~ -20V; (xxii) -20 ~ -10V; (xxiii) -10 ~ 0V; (xxiv) 0 ~ 10V; (xxv) 10 ~ 20V; (xxvi) 20 ~ 30V; (xxvii) 30 ~ 40V; (xxviii) 40 ~ 50V; (xxix) 50 ~ 60V; (xxx) 60 ~ 70V; (xxxi) 70 ~ 80V; (xxxii) 80 ~ 90V; (xxxiii) 90 ~ 100V; (xxxiv) 100 ~ 200V (xxxv) 200 ~ 300V; (xxxvi) 300 ~ 400V; (xxxvii) 400 ~ 500V; (xxxviii) 500 ~ 600V; (xxxix) 600 ~ 700V; (xl) 700 ~ 800V; (xli) 800 ~ 900V; (xlii) 900 ~ 1000V; (xliii) 1-2kV; (xliv) 2-3kV; (xlv) 3 ~ 4kV; and (xlvi) 4 ~ 5kV.

According to less preferred embodiments, the target can be maintained at a potential of <-5 kV or> 5 kV.

The mass spectrometer further includes a control system. The control system is configured and adapted to (i) switch the polarity of the target during a single experiment run, or (ii) repeatedly switch the polarity of the target during a single experiment run. To.

According to embodiments, the control system can be configured and adapted to repeatedly switch the polarity of the target at the following intervals: 0-10ms, 10-20ms, 20-30ms, 30-40ms, 40. ~ 50ms, 50 ~ 60ms, 60 ~ 70ms, 70 ~ 80ms, 80 ~ 90ms, 90 ~ 100ms, 100 ~ 200ms, 200 ~ 300ms, 300 ~ 400ms, 400 ~ 500ms, 500 ~ 600ms, 600 ~ 700ms, 700 ~ 800ms , 800 ~ 900ms, 900 ~ 1000ms, 1-2s, 2-3s, 3 ~ 4s or 4 ~ 5s.

According to another embodiment, the control system may use retention time switching. According to embodiments, the polarity of the target can be switched repeatedly at the following intervals: 0 to 1 minute, 1 to 2 minutes, 2 to 3 minutes, 3 to 4 minutes, 4 to 5 minutes, 5 to 6 minutes, 6-7 minutes, 7-8 minutes, 8-9 minutes, 9-10 minutes or> 10 minutes.

The mass spectrometer preferably further includes a housing. The housing includes a nebulizer, a target and an ion inlet device. The ion inlet device leads to the first vacuum stage of the mass spectrometer.

According to embodiments, the ion inlet device is an on-orvo, an ion inlet cone, an ion inlet capillary, an ion inlet heating capillary, an ion tunnel, an ion mobility spectrometer or separator, a differential ion mobility spectrometer, an asymmetric field ion transfer. It may include a degree spectrometer (FAIMS) device or other ion inlet.

The outlet of the first tube preferably has a diameter D and the spray of the analyte droplet is preferably configured to collide with the target collision zone.

The collision zone preferably has a maximum dimension x and the x / D ratios are <2, 2-5, 5-10, 10-15, 15-20, 20-25, 25-30, 30- It ranges from 35, 35-40 or> 40.

The collision zone preferably has an area selected from the group consisting of: (i) <0.01 mm²; (ii) 0.01 ~ 0.10mm²(Iii) 0.10 ~ 0.20mm²; (iv) 0.20 ~ 0.30mm²; (v) 0.30 ~ 0.40mm²; (vi) 0.40 ~ 0.50mm²; (vii) 0.50 ~ 0.60mm²; (viii) 0.60 ~ 0.70mm²; (ix) 0.70 ~ 0.80mm²; (x) 0.80 ~ 0.90mm²; (xi) 0.90 ~ 1.00mm²; (xii) 1.00 ~ 1.10mm²; (xiii) 1.10 ~ 1.20mm²; (xiv) 1.20 ~ 1.30mm²; (xv) 1.30 ~ 1.40mm²; (xvi) 1.40 ~ 1.50mm²; (xvii) 1.50 ~ 1.60mm²; (xviii) 1.60 ~ 1.70mm²; (xix) 1.70 ~ 1.80mm²; (xx) 1.80 ~ 1.90mm²; (xxi) 1.90 ~ 2.00mm²; (xxii) 2.00 ~ 2.10mm²; (xxiii) 2.10 ~ 2.20mm²; (xxiv) 2.20 ~ 2.30mm²; (xxv) 2.30 ~ 2.40mm²; (xxvi) 2.40 ~ 2.50mm²; (xxvii) 2.50 ~ 2.60mm²; (xxviii) 2.60 ~ 2.70mm²; (xxix) 2.70 ~ 2.80mm²; (xxx) 2.80 ~ 2.90mm²; (xxxi) 2.90 ~ 3.00mm²; (xxxii) 3.00 ~ 3.10mm²; (xxxiii) 3.10 ~ 3.20mm²; (xxxiv) 3.20 ~ 3.30mm²; (xxxv) 3.30 ~ 3.40mm²; (xxxvi) 3.40 ~ 3.50mm²; (xxxvii) 3.50 ~ 3.60mm²; (xxxviii) 3.60 ~ 3.70mm²; (xxxix) 3.70 ~ 3.80mm²; (xl) 3.80 ~ 3.90mm²; And (xli) 3.90 ~ 4.00mm²。

The target is preferably a first distance X in a first direction from the ion inlet device following the first vacuum step of the mass spectrometer.₁A second distance Z in the second direction from the ion inlet device₁Placed in. The second direction is orthogonal to the first direction. (i) X₁Is selected from the group consisting of: (i) 0 ~ 1mm; (ii) 1-2mm; (iii) 2 ~ 3mm; (iv) 3 ~ 4mm; (v) 4 ~ 5mm; (vi) 5 ~ 6mm; (vii) 6 ~ 7mm; (viii) 7 ~ 8mm; (ix) 8 ~ 9mm; (x) 9 ~ 10mm; and (xi)> 10mm; and / or (ii) Z₁Is selected from the group consisting of: (i) 0 ~ 1mm; (ii) 1-2mm; (iii) 2 ~ 3mm; (iv) 3 ~ 4mm; (v) 4 ~ 5mm; (vi) 5 ~ 6mm; (vii) 6 ~ 7mm; (viii) 7 ~ 8mm; (ix) 8 ~ 9mm; (x) 9 ~ 10mm; and (xi)> 10mm.

The target is preferably positioned so as to deflect the flow of the analyte droplet and / or the analyte ion towards the ion inlet device of the mass spectrometer.

According to embodiments, the ion inlet device includes an ion orifice, an ion inlet cone, an ion inlet capillary, an ion inlet heating capillary, an ion tunnel, an ion mobility spectrometer or separator, a differential ion mobility spectrometer, an asymmetric field ion transfer. It may include a degree spectrometer (FAIMS) device or other ion inlet.

The target is preferably located upstream of the ion inlet device of the mass spectrometer, thereby deflecting the ions towards the ion inlet device.

Targets preferably include either (i) rods or (ii) pins with tapered cones. The flow of analyte droplets either causes the rod or tapered cone of the pin to collide directly on the centerline of the rod or pin, or (ii) faces the ion inlet orifice of the mass spectrometer of the rod or tapered cone. It is arranged so as to collide with the side facing the separation direction.

Ion sources preferably include atmospheric pressure ionized (API) ion sources.

Targets preferably include stainless steel targets, metals, gold, non-metallic materials, semiconductors, other materials including metal or carbide coatings, insulators or ceramics.

According to embodiments, the target may include multiple plates such that droplets from the atomizer cascade on multiple target plates and / or target is placement configuration d ~ have multiple collision points ssothat multiple. The droplets are arranged to have a plurality of collision points so that the droplets are ionized by the obliquely deflecting ions.

According to embodiments, the target comprises one or more mesh or grid targets.

Grid or mesh targets with grid or mesh collision surfaces have been found to be particularly advantageous compared to using pin targets. This is because when a grid or mesh target is used, the position-dependent problem that can occur when a non-hollow pin is used as a target is solved.

The one or more mesh or grid targets preferably include one or more wire mesh or grid targets.

The wire mesh or grid target preferably comprises a wire having a diameter selected from the group consisting of: (i) <50 μm; (ii) 50-100 μm; (iii) 100-150 μm; (iv) 150-200 μm (v) 200-250 μm; (vi) 250-300 μm; (vii) 300-350 μm; (viii) 350-400 μm; (ix) 400-450 μm; (x) 450-500 μm; (xi) 500-550 μm; (xii) 550 ~ 600 μm; (xiii) 600 ~ 650 μm; (xiv) 650 ~ 700 μm; (xv) 700 ~ 750 μm; (xvi) 750 ~ 800 μm; (xvii) 800 ~ 850 μm; (xviii) 850 ~ 900 μm; xix) 900 ~ 950 μm; (xx) 950 ~ 1000 μm; and (xxi)> 1 mm.

The mesh or grid preferably has a spacing selected from the group consisting of: (i) <50 μm; (ii) 50-100 μm; (iii) 100-150 μm; (iv) 150-200 μm; (v) ) 200 ~ 250 μm; (vi) 250 ~ 300 μm; (vii) 300 ~ 350 μm; (viii) 350 ~ 400 μm; (ix) 400 ~ 450 μm; (x) 450 ~ 500 μm; (xi) 500 ~ 550 μm; (xii) 550 ~ 600 μm; (xiii) 600 ~ 650 μm; (xiv) 650 ~ 700 μm; (xv) 700 ~ 750 μm; (xvi) 750 ~ 800 μm; (xvii) 800 ~ 850 μm; (xviii) 850 ~ 900 μm; (xix) 900 ~ 950 μm; (xx) 950 ~ 1000 μm; and (xxi)> 1 mm.

One or more mesh or grid targets are preferably placed in one of the following planes: (i) a plane substantially perpendicular to the spray axis of one or more sprayers or (ii) 1 A surface tilted at an angle of <90 ° with respect to the spray axis of one or more sprayers.

One or more mesh or grid targets preferably provide multiple collision zones.

One or more mesh or grid targets preferably include a rift or opening in a one-dimensional or two-dimensional array.

One or more mesh or grid targets preferably include multiple layers.

One or more of the layers preferably comprises a mesh or grid.

The plurality of layers preferably include layers having substantially the same or substantially different mesh sizes.

According to embodiments, the mass spectrometer further comprises a vibrating device arrangement configuration and is adapted to vibrate the target.

The use of piezoelectric vibrations applied to the impactor bar or target is particularly advantageous as the vibrations of the target can assist in the reduction of second droplets through surface decay. The use of piezoelectric vibration is also particularly advantageous as it is recommended by liquid beading.

The source of vibration is preferably arranged and adapted to vibrate the target and reduce the size of the resulting second droplet through surface decay.

The vibration source preferably includes a piezoelectric vibration source.

The source of vibration is preferably arranged and adapted to vibrate the target at a frequency f selected from the group consisting of: (i) <1kHz; (ii) 1-2kHz; (iii) 2~. 3kHz; (iv) 3 ~ 4kHz; (v) 4 ~ 5kHz; (vi) 5 ~ 6kHz; (vii) 6 ~ 7kHz; (viii) 7 ~ 8kHz; (ix) 8 ~ 9kHz; (x) 9 ~ 10kHz (xi) 10 ~ 11kHz; (xii) 11 ~ 12kHz; (xiii) 12 ~ 13kHz; (xiv) 13 ~ 14kHz; (xv) 14 ~ 15kHz; (xvi) 15 ~ 16kHz; (xvii) 16 ~ 17kHz; (xviii) 17 ~ 18kHz; (xix) 18 ~ 19kHz; (xx) 19 ~ 20kHz; and (xxi)> 20kHz.

According to embodiments, the mass spectrometer preferably further comprises a first apparatus. The first device is arranged and adapted to rotate and / or translate the target.

As those skilled in the art will understand, when performing ion generation by collision of fast droplets onto a target, target positioning is important for obtaining acceptable levels of signal strength. According to a particularly preferred embodiment, it is possible to achieve an average more stable signal intensity when the target (eg, eccentric path) is rotated relative to the spray of high speed droplets. As a result, the overall or average ion signal can be stabilized and is also affected by large fluctuations in the intensity of the generated analytical ion, which depends on the exact position of the target relative to the fast spray of droplets. It becomes difficult.

Targets preferably include pins or rods.

The target preferably has a first central longitudinal axis, and the first device is configured and adapted to rotate the target around the second axis. The second axis is displaced or offset from the first axis.

The first device is preferably arranged and adapted to rotate the target around a substantially eccentric or non-circular path or on a substantially eccentric or non-circular path in use.

The first device is preferably configured and adapted to rotate the target at the following speeds: (i) <1rev / s; (ii) 1-2rev / s; (iii) 2-3rev / s; (iv) 3 ~ 4rev / s; (v) 4 ~ 5rev / s; (vi) 5 ~ 6rev / s; (vii) 6 ~ 7rev / s; (viii) 7 ~ 8rev / s; (ix) 8 ~ 9rev / s; (x) 9 ~ 10rev / s; (xi)> 10rev / s; (xii) <1rpm; (xiii) 1 ~ 5rpm; (xiv) 5 ~ 10rpm; (xv) 10 ~ 15rpm; (xvi) 15 ~ 20rpm; (xvii) 20 ~ 25rpm; (xviii) 25 ~ 30rpm; (xix) 30 ~ 35rpm; (xx) 35 ~ 40rpm; (xxi) 40 ~ 45rpm; (xxii) 45 ~ 50rpm; ( xxiii) 50 ~ 60rpm; (xxiv) 60 ~ 70rpm: (xxv) 70 ~ 80rpm; (xxvi) 80 ~ 90rpm; (xxvii) 90 ~ 100rpm; (xxviii) 100 ~ 150rpm; (xxix) 150 ~ 200rpm; (xxx ) 200 ~ 250rpm; and (xxxi)> 250rpm.

The first device is preferably arranged and adapted to rotate the target substantially continuously.

The first device is preferably arranged and adapted to rotate the target substantially continuously over at least period T. T is selected from the following groups: (i) <1s; (ii) 1 ~ 5s; (iii) 5 ~ 10s; (iv) 10 ~ 15s; (v) 15 ~ 20s; (vi) 20 ~ 25s; (vii) 25 ~ 30s; (viii) 30 ~ 35s; (ix) 35 ~ 40s; (x) 40 ~ 45s; (xi) 45 ~ 50s; (xii) 50 ~ 55s; (xiii) 55 ~ 60s; and (xiv)> 60s.

The mass spectrometer preferably includes a control system. The control system is configured and adapted to monitor the analyte signal as a function of the target location or as opposed to the target location.

The control system is preferably arranged and adapted to rotate the device and / or translate the target to the desired position to optimize the analyte ion signal or control the intensity of the analyte ion. Will be done.

The control system is preferably arranged and adapted to rotate or / or translate the target between a plurality of desired positions to alter or control the intensity of the analyte ion.

According to aspects of the invention, there is provided a mass spectrometric method that includes: To provide a separator configured and adapted to release the eluent over time, the separators are (i) capillary electrophoresis (CE) separators, (ii) capillary electronic chromatographs. Includes either a imaging (CEC) separator, (iii) a substantially rigid ceramic-based multilayer microfluidic substrate (ceramic tile) separator, or (iv) a supercritical fluid chromatography separator. That and Providing a target and By spraying the eluate released from the separator, the flow of the analyte droplets is directed and collided with the target to ionize the analyte to form multiple analyte ions.

According to embodiments, the mass spectrometer may further include: (a) Further ion sources selected from the group consisting of: (i) electron spray ionization (ESI) ion source; (ii) atmospheric photoionization (APPI) ion source; (iii) atmospheric chemistry Ionization ("APCI") Ion source; (iv) Matrix-assisted laser desorption ionization ("MALDI") ion source; (v) Laser desorption ionization ("LDI") ion source; (vi) Atmospheric pressure ionization ("API") ) Ion source; (vii) Desorption / ionization on silicon (DIOS) Ion source; (viii) Electron collision (EI) Ion source; (ix) Chemical ionization (CI) Ion source; (x) Field Ionization (FI) Ion Source; (xi) Field Desorption (FD) Ion Source; (xii) Induced Bonded Plasma (ICP) Ion Source; (xiii) Fast Atomic Impact (FAB) Ion Source; (xiv) Liquid Secondary Ion Mass Analysis ("LSIMS") Ion Source; (xv) Desorption Electron Spray Ionization ("DESI") Ion Source; (xvi) Nickel-63 Radioactive Ion Source; (xvii) Atmospheric Pressure Matrix Assisted Laser Desorption Ion Source; (xviii) Thermospray Ion Source; (xix) Atmospheric Sampling Glow Discharge Ion Source (ASGDI) Ion Source; (xx) Glow Discharge (GD) Ion Source; and (xxi) Impactor Ion sources; and / or (b) One or more continuous or pulsed ion sources s; and / or (c) One or more ion guides and / or (d) One or more ion mobility separators and / or one or more asymmetric field ion mobility spectrometers and / or (e) One or more ion traps or one or more ion trapping regions and / or (f) One or more collisions, fragmentation or reaction cells selected from the group consisting of:(i) Collision-induced dissociation (CID) fragmentation device, (ii) Surface-induced dissociation (SID) fragmentation device, (iii) Ion transfer divergence (ETD) fragmentation device, (iv) Ion capture dissociation ( ECD ") Fragmentation device, (v) Ion collision or collision dissociation fragmentation device, (vi) Photo-induced dissociation (" PID ") Fragmentation device, (vii) Laser-induced dissociation fragmentation device, (viii) Infrared radiation-induced dissociation device, ( ix) Ultraviolet radiation-induced dissociation device, (x) Nozzle skimmer interface fragmentation device, (xi) In-source fragmentation device, (xii) In-source collision-induced dissociation fragmentation device, (xiii) Heat or temperature source fragmentation device, (xiv) Electric field Induced Fragmentation Equipment, (xv) Magnetic Field Induced Fragmentation Equipment, (xvi) Enzyme Digestion or Enzyme Decomposition Fragmentation Equipment, (xvii) Ion-Ion Reaction Fragmentation Equipment, (xviii) Ion Molecular Reaction Fragmentation Equipment, (xix) Ion Atomic Reaction Fragmentation Equipment , (Xx) ion semi-stable ion reaction fragmentation device, (xxi) ion semi-stable molecular reaction fragmentation device, (xxii) ion semi-stable atomic reaction fragmentation device, (xxiii) reach the ion to generate an addition ion or a generated ion. Ion-ion reactor for (xxiv) ion to generate adduct or product ion, ion molecule reactor for reaching (xxv) ion to generate adduct or product ion Atomic reactor, ion semi-stable ion reactor for reaching (xxvi) ions to generate adduct or generated ions, ion semi-stable for reaching (xxvii) ions to generate adducts or generated ions Molecular reactor, ion semi-stable atom for reaching the (xxviii) ion to generate an addition or production ionReactor, and (xxix) electron ionization dissociation (EID) fragmentation device, and / or (g) Mass spectrometer selected from the following group: (i) Quadrupole mass spectrometer, (ii) 2D or linear quadrupole mass spectrometer, (iii) Pole or 3D quadrupole mass spectrometer , (Iv) Penning Trap Mass Spectrometer, (v) Ion Trap Mass Spectrometer, (vi) Magnetic Field Mass Spectrometer, (vii) Ion Cyclotron Resonance ("ICR") Mass Analyzer, (viii) Fourier Transform Ion Cyclotron Resonance (FTICR) mass spectrometer, (ix) electrostatic or orbitrap mass spectrometer, (x) Fourier transform electrostatic or orbittrap mass spectrometer, (xi) Fourier transform mass spectrometer, (xii) flight time Mass spectrometer, (xiii) orthogonal accelerated flight time mass spectrometer, and (xiv) linear accelerated flight time mass spectrometer, and / or (h) One or more analyzers or electrostatic analyzers, and / or (i) One or more ion detectors and / or (j) One or more mass filters selected from the group consisting of: (i) quadrupole mass filters, (ii) 2D or linear quadrupole ion traps, (iii) poles or 3D quadrupole ion traps , (Iv) Penning ion trap, (v) Ion trap, (vi) Magnetic mass filter, (vii) Time-of-flight mass filter, and (viii) Wien filter, and / or (k) A device or ion gate for pulsing ions, and / or (l) A device that converts a substantially continuous ion beam into a pulsed ion beam.

The mass spectrometer may include one of the following: (i) C-trap and Orbitrap (RTM) mass spectrometers that include an outer barrel-shaped electrode and a coaxial inner spindle-shaped electrode, in which in the first mode of operation, ions are sent to the C-trap and then Orbitrap. (RTM) Infused into a mass spectrometer, in the second mode of operation, the ions are sent to the C trap and then to the collision cell or electron transfer dissociator, and at least some of the ions are fragmented and fragmented. The fragment ions are then sent to the C trap and injected into the Orbitrap (RTM) mass spectrometer, the C trap and the Orbitrap (RTM) mass spectrometer, and / or. (ii) A stack-type ring ion guide containing a plurality of electrodes, each of the plurality of electrodes has an aperture that serves as a passage for sending ions during use, and the spacing of the electrodes is the length of the ion path. The aperture in the electrode in the upstream part of the ion guide has a first diameter, and the aperture in the electrode in the downstream part of the ion guide has a second diameter smaller than the first diameter. A stack-type ring ion guide in which the opposite phase of the AC or RF voltage is applied to the continuous electrodes during use.

Hereinafter, various embodiments of the present invention will be described solely for the purpose of exemplification with reference to the accompanying drawings.

<figref num="1">An impactor spray API source according to an embodiment of the present invention is shown.</figref><figref num="2a">Indicates an impactor spray source.</figref><figref num="2b">Shows an optimized impactor spray source.</figref>

FIG. 1 is a schematic diagram of a general layout of an impactor spray API source according to a preferred embodiment. Liquid flow from the CE column outlet (or other separator) enters the atomizer probe 1 and is delivered to the atomizer tip 2 via the inner capillary tube 3. The inner capillary 3 is surrounded by a second concentric capillary 4. The second concentric capillary 4 delivers a liquid constituent stream. The constituent flow of this liquid is mixed with the flow from the first capillary 3 at the probe tip. The second capillary tube 4 is surrounded by a third concentric capillary 5. The third concentric capillary 5 includes a gas inlet 6 for delivering a high speed flow to the outlets of the liquid capillaries 3 and 4.

The spray spray produced by this arrangement configuration contains a liquid with a typical diameter of 10-20 μm and a velocity of more than 100 m / s at a nearby distance from the sprayer tip 2. The resulting droplet is heated by an additional gas stream that enters the concentric heater 7 through the second gas inlet 8.

The atomizer is preferably hinged to the right hand side of the mass spectrometer ion inlet cone 9 and swings to vary the horizontal distance between the atomizer tip 2 and the mass spectrometer ion inlet orifice 10. it can. The probe is also configured to be capable of varying the vertical distance between the atomizer tip 2 and the ion inlet orifice 10. The relative tips of the inner capillaries 3, the second capillaries 4 and the third capillaries 5 can be adjusted. According to the embodiment, the capillaries 3, 4 and 5 can be arranged and configured so as to be coplanar with each other. According to another embodiment, the capillaries 3, 4 and 5 can be arranged and configured such that one or more capillaries 3, 4 and 5 project or concave from each other.

Targets 11 of similar dimensions to the liquid capillary are preferably located between the atomizer tip 2 and the ion inlet orifice 10. Target 11 can be manipulated in the x and y directions (in the horizontal plane) via the microadjuster step and typically holds at a potential of 0-5 kV with respect to the source enclosure 12 and the ion inlet orifice 10. be able to. During operation, the ion inlet cone 10 is surrounded by the metal cone gas housing 13. The metal cone gas housing 13 is coplanar with the flow of nitrogen gas entering through the t gas inlet 14. All gas entering the source enclosure must exit through the source enclosure exhaust 15 or ion inlet orifice 10 pumped by the first vacuum step 16 of the mass spectrometer.

FIG. 2a is a schematic plan view of the impactor spray source, with the grounded atomizer probe omitted from the figure. The impactor target 11 includes a stainless steel rod or pin having an outer diameter of typically 1-2 mm. The rod or pin 11 is typically a horizontal distance X of 5 mm from the ion inlet orifice 10₁Placed in. By fine-tuning the tip of the probe, it is possible to sweep on the target surface until the optimum collision point for maximum sensitivity is obtained. A typical optimization position is shown in the schematic diagram of FIG. 2b. In the figure, offset X₂Is about 0.4 mm.

Figure 2b also shows the vertical position and target of the probe in a preferred embodiment (ie, Z).₁= 9mm and Z₂= 3mm).

In a preferred embodiment, the source is operated at the following bias potentials: atomizer = 0V, impactor target = 1.0kV, ion inlet cone = 100V and cone gas housing = 100V. The heater assembly and source enclosure are preferably maintained at ground potential. The source can be operated with the following gas flow settings: nitrogen atomizer gas heated to 7 bar, nitrogen heater gas flow = 1200 L / hr and nitrogen cone gas flow = 150 L / hour.

Suitable embodiments can be used in other applications that can be easily simplified by the use of grounded atomizer probes such as capillary electronic chromatography (CEC) and tile-based microchip LC / MS systems.

Tile-based microchip LC systems preferably include a substantially rigid ceramic-based multilayer microfluidic substrate (also referred to as "ceramic tile"). See US 2009/0321 35. The contents of this document are incorporated herein by reference. For protein samples, the ceramic may include co-fired ceramics (HTCC), which allows for suitable low levels of sample loss due to the attachment of the sample walls of the conduit within the substrate. Within the layers of the substrate, there is a path that acts as a separation column. Apertures in the sides of the substrate allow the openings to have a path through which fluid can be introduced into the column. The fluid that has passed through the aperture towards the electron spray ejector under high pressure is coupled at the outlet end of the path. A hole in the side of the microfluidic cartridge provides a fluid inlet port for fluid delivery to the substrate. Each fluid inlet port is aligned with one of the fluid apertures and surrounds one of the fluid apertures.

It is also possible to implement the preferred embodiment as an interface for supercritical fluid chromatography / MS.

Collision ion-based sprays with target pins are illustrated as providing improved ionization efficiencies for both polar and non-polar compounds compared to standard ESI or APCI. However, it has been observed that the performance of different mobile phase compositions may reasonably strongly depend on the physical geometry of the probe and pin.

Due to the position dependence of probes and pins on relative performance in high organic mobile phases, it can be difficult to achieve the required tolerances. Moreover, maintaining these tolerances can be difficult. This is because the pins and / or probe capillaries may need to be replaced more than once over the life of the instrument.

According to embodiments of the present invention, it is preferred to use grid or mesh targets instead of pin targets. It has been found that using a grid or mesh target with a grid or mesh collision surface is particularly advantageous over using a pin target. This is because when a grid or mesh target is used, the problem of position dependence that occurs when a non-hollow pin is used as a target is solved.

It is preferable to use a mesh or grid target of appropriate size as the collision target. According to a preferred embodiment, the collision zone (ie, the plume diameter at the point of collision with the collision with the target) is preferably 0.5-1.0 mm.

According to a preferred embodiment, the mesh wire size and spacing are preferably sized so that several separate collision zones are obtained within the collision zone or region. The wire diameter may preferably be large enough to allow collision of plumes on the wire and improve spraying. Spacing the mesh by 150 μm and wire diameter of 100 μm has proven to be particularly advantageous. However, other aspect ratios are also contemplated and are within the scope of the present invention. According to embodiments, the mesh or grid may include a substantially flat rectangle (15 mmx7 mm) and may be held substantially perpendicular to the spray axis. According to this embodiment, the spray is substantially carried out through a mesh or grid.

Alternatively, the mesh or grid may be angled with respect to the spray axis. The angle of the mesh or grid can be set to deflect towards or near the mass spectrometer inlet as the plume passes through the mesh or grid. The mesh or grid target can be configured at a 70 ° angle to the spray axis.

The physical dimensions of the mesh or grid are preferably set or arranged so that liquid beading on the surface of the mesh or grid can be suitably minimized. The angle and shape of the mesh or grid can be optimized to reduce liquid beading.

According to a preferred embodiment, a high voltage mesh or grid electrode can be added to assist ionization in a manner similar to other embodiments of the invention using the pin targets described above. According to embodiments, the mesh or grid can be held at a potential of 1 kV. However, it will be apparent to those skilled in the art that the mesh or grid target may be maintained at other potentials.

A particular advantage when using a mesh or grid target is that the dependence on geometry is significantly reduced for a mesh or grid target according to a preferred embodiment. This is because the flow of droplets collides on multiple collision points on the mesh or grid target. As the probe or mesh target moves, the impact properties of the droplets on the target remain substantially the same. Therefore, the ion source performance relative to the MS inlet and probe positions behaves similarly to an electron spray ionization (ESI) ion source with respect to the ion inlet.

Further embodiments are also contemplated. For example, a grid may be used instead of the mesh. The grid preferably has multiple collision points within the zone where the droplet flow collides with the target. A single row grid can be used if post-collision spray orientation position dependence is required.

According to embodiments, the target may include multiple layered meshes and / or grids to achieve the same effect as when angled a single layer mesh or grid target.

According to the embodiment, the surface ionized impactor bar or target as described above can be further improved by having the piezoelectric vibrating device and vibrating the wisdom bar or target. The vibration of the bar or target where surface ionization occurs on its surface helps reduce the size of the second droplet, resulting in an increased rate of solvent evaporation and a support for signal response.

According to a preferred embodiment, the impactor bar or target is placed within the source enclosure. In this configuration, the capillary is preferably grounded and the potential is preferably applied to the impactor bar or target and sample cone inlet structure. By integrating the impactor spray with the separator, potentials for the generation of non-polar, highly polar, single-charge and / or polyvalent vapor phase ions are introduced into the mass spectrometer for analysis. However, the ionization process and fluid dynamics can be different, which can result in the formation of larger droplets. The use of piezoelectric vibrations applied to the impactor bar or target is particularly advantageous as it helps reduce the resulting second droplets.

Those skilled in the art will appreciate that the mechanism of droplet formation in pneumatically assisted sprays is not important and cannot be approximated by a particular model with known boundary conditions. There is no single process that seems to work universally for droplet formation, and the initial spray produced changes rapidly due to second fragmentation and recombination and coalescence. It is preferable to apply piezoelectric vibrations to the impactor bar or target to support reduction through surface decay of the resulting second droplet.

According to the embodiment, it is preferable to utilize the target pin. The target pin is preferably rotated, for example, on an eccentric path so that an easily reproducible level of ionic signal is obtained. According to embodiments, the target pins or rods are preferably placed or mounted off-axis from the axis of rotation. The pin or rod target is preferably arranged or configured to be within the path of the fast droplets emitted from the atomizer. The droplets emitted from the atomizer are arranged to collide on a pin or rod target, which produces ions for analysis by mass spectrometry. The rotational position of the pin or rod is preferably controlled through a computer controlled motor.

According to embodiments, the analyte signal can be monitored for pin or rod position. The pins or rods can then be rotated or set to specific positions under computer control to maximize signal strength. Other embodiments are also contemplated. That is, it is possible to control the intensity of the analyte ion produced by rotating the pin or rod between one or more different rotation positions, or to control the analyte ion generation efficiency.

The central longitudinal axis of the pin or rod is preferably configured to be eccentric with respect to the central longitudinal axis of the rotating shaft. According to the embodiment, the position of the pin or rod may be changed by about 0.7 mm when the pin or rod target rotates once.

According to a less preferred embodiment, the position of the pin or rod target 10 may be translated rather than rotated (or the pin or rod target may be rotated and translated).

Those skilled in the art will appreciate that positioning the target is important for obtaining acceptable levels of signal strength in performing ion generation by impacting high speed droplets onto the target. According to a particularly preferred embodiment, it is possible to achieve average signal strength by rotating the target on the eccentric path relative to the spray of high speed droplets. As a result, the overall or average ion signal can be stabilized, and it can be made less susceptible to fluctuations in the intensity of the analyte ion depending on the exact position of the target relative to the droplet.

Although the present invention has been described with reference to preferred embodiments, those skilled in the art will appreciate various changes in embodiments and details that deviate from the scope of the invention as described in the appended claims. Understand that it is possible without.<u style="single">[Item of invention]</u><u style="single">[Item 1]</u><u style="single"> It s a mass spectrometer,</u><u style="single"> A separator configured and adapted to release the eluent over time, said separator: (i) capillary electrophoresis (CE) separator, (ii) capillary electronic chromatography (ii) With a separator, including either a CEC)) separator, (iii) a substantially rigid ceramic-based multilayer microfluidic substrate (ceramic tile) separator, or (iv) a supercritical fluid chromatography separator. ,</u><u style="single"> With a sprayer</u><u style="single"> With the target</u><u style="single"> Including</u><u style="single"> The eluent discharged from the separator is sprayed by the nebulizer during use to direct the flow of analyte droplets and collide with the target to ionize the analyte to produce a plurality of analyte ions. Form.</u><u style="single">Mass spectrometer.</u><u style="single">[Item 2]</u><u style="single"> The separator includes a capillary electrophoresis (CE) separator, the inlet end of the capillary electrophoresis separator is maintained at a first potential, and the outlet end of the capillary electrophoresis separator is a second. The mass spectrometer according to item 1, which is maintained at an electric potential.</u><u style="single">[Item 3]</u><u style="single"> The mass spectrometer according to item 1 or 2, wherein the separator comprises or is connected to a first tube.</u><u style="single">[Item 4]</u><u style="single"> The mass spectrometer according to item 3, wherein the first tube includes a capillary tube.</u><u style="single">[Item 5]</u><u style="single"> The outlet of the first tube is maintained at potential within the following range during use: (i) -5 ~ -4kV; (ii) -4 ~ -3kV; (iii) -3 ~ -2kV (iv) -2 ~ -1kV; (v) -1000 ~ -900V; (vi) -900 ~ -800V; (vii) -800 ~ -700V; (viii) -700 ~ -600V; (ix)- 600 ~ -500V; (x) -500 ~ -400V; (xi) -400 ~ -300V; (xii) -300 ~ -200V; (xiii) -200 ~ -100V; (xiv) -100 ~ -90V; (xv) -90 ~ -80V; (xvi) -80 ~ -70V; (xvii) -70 ~ -60V; (xviii) -60 ~ -50V; (xix) -50 ~ -40V; (xx) -40 ~ -30V; (xxi) -30 ~ -20V; (xxii) -20 ~ -10V; (xxiii) -10 ~ 0V; (xxiv) 0 ~ 10V; (xxv) 10 ~ 20V; (xxvi) 20 ~ 30V (xxvii) 30 ~ 40V; (xxviii) 40 ~ 50V; (xxix) 50 ~ 60V; (xxx) 60 ~ 70V; (xxxi) 70 ~ 80V; (xxxii) 80 ~ 90V; (xxxiii) 90 ~ 100V; (xxxiv) 100 ~ 200V; (xxxv) 200 ~ 300V; (xxxvi) 300 ~ 400V; (xxxvii) 400 ~ 500V; (xxxviii) 500 ~ 600V; (xxxix) 600 ~ 700V; (xl) 700 ~ 800V; xli) 800 ~ 900V; (xlii) 900 ~ 1000V; (xliii) 1-2kV; (xliv) 2-3kV; (xlv) 3 ~ 4kV; and (xlvi) 4 ~ 5kV, mass according to item 3 or 4. Analyzer.</u><u style="single">[Item 6]</u><u style="single"> The first tube is surrounded by a second tube and the second tube is arranged to provide a liquid flow that mixes with the eluent discharged from the outlet of the first tube. And the mass spectrometer according to item 3, 4 or 5, which is adapted.</u><u style="single">[Item 7]</u><u style="single"> The mass spectrometer according to item 6, wherein the second tube includes a capillary tube.</u><u style="single">[Item 8]</u><u style="single"> The ends of the first and second tubes are (i) coplanar or parallel to each other, or (ii) projecting, concave or non-parallel to each other. The mass spectrometer according to item 7.</u><u style="single">[Item 9]</u><u style="single"> Item 3-8, further comprising a third tube, wherein the third tube is configured and adapted to provide gas flow to the outlet and / or the second tube of the first tube. The mass spectrometer according to any one item.</u><u style="single">[Item 10]</u><u style="single"> The mass spectrometer according to item 9, wherein the third tube includes a capillary tube.</u><u style="single">[Item 11]</u><u style="single"> The mass spectrometer according to item 9 or 10, wherein the third tube surrounds the second tube and / or is concentric with the first and second tubes.</u><u style="single">[Item 12]</u><u style="single"> The ends of the first tube, the second tube and the third tube are (i) coplanar or parallel to each other, or (ii) projecting or concave from each other. The mass spectrometer according to item 11, which is or is non-parallel.</u><u style="single">[Item 13]</u><u style="single"> The mass spectrometer according to item 9 or 10, wherein the third tube is not concentric with the first tube and the second tube.</u><u style="single">[Item 14]</u><u style="single"> Further including a heater, the heater is configured and adapted to supply a heated gas stream to heat the droplets emitted from the first tube and / or the second tube. , The mass spectrometer according to any one of items 3 to 13.</u><u style="single">[Item 15]</u><u style="single"> The target is located at &lt;10 mm, &lt;9 mm, &lt;8 mm, &lt;7 mm, &lt;6 mm, &lt;5 mm, &lt;4 mm, &lt;3 mm or &lt;2 mm from the outlet of the atomizer, any one of items 1 to 14. The mass spectrometer described in the section.</u><u style="single">[Item 16]</u><u style="single"> The target is maintained at the following potentials during use: (i) -5 ~ -4kV; (ii) -4 ~ -3kV; (iii) -3 ~ -2kV; (iv) -2 ~ -1kV (v) -1000 ~ -900V; (vi) -900 ~ -800V; (vii) -800 ~ -700V; (viii) -700 ~ -600V; (ix) -600 ~ -500V; (x)- 500 ~ -400V; (xi) -400 ~ -300V; (xii) -300 ~ -200V; (xiii) -200 ~ -100V; (xiv) -100 ~ -90V; (xv) -90 ~ -80V; (xvi) -80 ~ -70V; (xvii) -70 ~ -60V; (xviii) -60 ~ -50V; (xix) -50 ~ -40V; (xx) -40 ~ -30V; (xxi) -30 ~ -20V; (xxii) -20 ~ -10V; (xxiii) -10 ~ 0V; (xxiv) 0 ~ 10V; (xxv) 10 ~ 20V; (xxvi) 20 ~ 30V; (xxvii) 30 ~ 40V; ( xxviii) 40 ~ 50V; (xxix) 50 ~ 60V; (xxx) 60 ~ 70V; (xxxi) 70 ~ 80V; (xxxii) 80 ~ 90V; (xxxiii) 90 ~ 100V; (xxxiv) 100 ~ 200V; (xxxv) ) 200 ~ 300V; (xxxvi) 300 ~ 400V; (xxxvii) 400 ~ 500V; (xxxviii) 500 ~ 600V; (xxxix) 600 ~ 700V; (xl) 700 ~ 800V; (xli) 800 ~ 900V; (xlii) 900 ~ 1000V; (xliii) 1-2kV; (xliv) 2-3kV; (xlv) 3 ~ 4kV; and (xlvi) 4 ~ 5kV, the mass analyzer according to any one of items 1 to 15.</u><u style="single">[Item 17]</u><u style="single"> The mass spectrometer further includes a control system, which (i) switches the polarity of the target during a single experiment run or (ii) repeats the polarity of the target during a single experiment run. The mass spectrometer according to any one of items 1 to 16, which is arranged and adapted to make a switch.</u><u style="single">[Item 18]</u><u style="single"> The control system</u><u style="single"> (i) Repeatedly switching the polarity of the target is 0 to 10 ms, 10 to 20 ms, 20 to 30 ms, 30 to 40 ms, 40 to 50 ms, 50 to 60 ms, 60 to 70 ms, 70 to 80 ms, 80 to 90 ms, 90 to 90. 100ms, 100-200ms, 200-300ms, 300-400ms, 400-500ms, 500-600ms, 600-700ms, 700-800ms, 800-900ms, 900-1000ms, 1-2s, 2-3s, 3-4s or Do it at intervals of 4-5s and / or</u><u style="single"> (ii) By using retention time switching, the polarity of the target is 0 to 1 minute, 1 to 2 minutes, 2 to 3 minutes, 3 to 4 minutes, 4 to 5 minutes, 5 to 6 minutes, 6 It can be switched repeatedly at intervals of ~ 7 minutes, 7 ~ 8 minutes, 8 ~ 9 minutes, 9 ~ 10 minutes or&gt; 10 minutes,</u><u style="single">Arranged and adapted to do,</u><u style="single">The mass spectrometer according to item 17.</u><u style="single">[Item 19]</u><u style="single"> The mass according to any one of items 1 to 18, further comprising a housing for accommodating the atomizer, the target and the ion inlet device, wherein the ion inlet device is connected to a first vacuum stage of the mass spectrometer. Analyzer.</u><u style="single">[Item 20]</u><u style="single"> The ion inlet device includes an ion orifice, an ion inlet cone, an ion inlet capillary, an ion inlet heating capillary, an ion tunnel, an ion mobility spectrometer or a separator, a differential ion mobility spectrometer, and an asymmetric field ion mobility spectrometer ("" FAIMS ") The mass spectrometer according to item 19, including the device or other ion inlet.</u><u style="single">[Item 21]</u><u style="single"> The item according to any one of items 3 to 20, wherein the outlet of the first tube has a diameter D, and the spray of the analyte droplet is configured to collide with the collision zone of the target. Mass spectrometer.</u><u style="single">[Item 22]</u><u style="single"> The collision zone has the maximum dimension x, and the x / D ratios are &lt;2, 2-5, 5-10, 10-15, 15-20, 20-25, 25-30, 30-35, 35. The mass spectrometer according to item 21, which is in the range of ~ 40 or&gt; 40.</u><u style="single">[Item 23]</u><u style="single"> The collision zone has an area selected from the group consisting of: (i) &lt;0.01 mm</u>^{<u style="single">2</u>}<u style="single">; (ii) 0.01 ~ 0.10mm</u>^{<u style="single">2</u>}<u style="single">(Iii) 0.10 ~ 0.20mm</u>^{<u style="single">2</u>}<u style="single">; (iv) 0.20 ~ 0.30mm</u>^{<u style="single">2</u>}<u style="single">; (v) 0.30 ~ 0.40mm</u>^{<u style="single">2</u>}<u style="single">; (vi) 0.40 ~ 0.50mm</u>^{<u style="single">2</u>}<u style="single">; (vii) 0.50 ~ 0.60mm</u>^{<u style="single">2</u>}<u style="single">; (viii) 0.60 ~ 0.70mm</u>^{<u style="single">2</u>}<u style="single">; (ix) 0.70 ~ 0.80mm</u>^{<u style="single">2</u>}<u style="single">; (x) 0.80 ~ 0.90mm</u>^{<u style="single">2</u>}<u style="single">; (xi) 0.90 ~ 1.00mm</u>^{<u style="single">2</u>}<u style="single">; (xii) 1.00 ~ 1.10mm</u>^{<u style="single">2</u>}<u style="single">; (xiii) 1.10 ~ 1.20mm</u>^{<u style="single">2</u>}<u style="single">; (xiv) 1.20 ~ 1.30mm</u>^{<u style="single">2</u>}<u style="single">; (xv) 1.30 ~ 1.40mm</u>^{<u style="single">2</u>}<u style="single">; (xvi) 1.40 ~ 1.50mm</u>^{<u style="single">2</u>}<u style="single">; (xvii) 1.50 ~ 1.60mm</u>^{<u style="single">2</u>}<u style="single">; (xviii) 1.60 ~ 1.70mm</u>^{<u style="single">2</u>}<u style="single">; (xix) 1.70 ~ 1.80mm</u>^{<u style="single">2</u>}<u style="single">; (xx) 1.80 ~ 1.90mm</u>^{<u style="single">2</u>}<u style="single">; (xxi) 1.90 ~ 2.00mm</u>^{<u style="single">2</u>}<u style="single">; (xxii) 2.00 ~ 2.10mm</u>^{<u style="single">2</u>}<u style="single">; (xxiii) 2.10 ~ 2.20mm</u>^{<u style="single">2</u>}<u style="single">; (xxiv) 2.20 ~ 2.30mm</u>^{<u style="single">2</u>}<u style="single">; (xxv) 2.30 ~ 2.40mm</u>^{<u style="single">2</u>}<u style="single">; (xxvi) 2.40 ~ 2.50mm</u>^{<u style="single">2</u>}<u style="single">; (xxvii) 2.50 ~ 2.60mm</u>^{<u style="single">2</u>}<u style="single">; (xxviii) 2.60 ~ 2.70mm</u>^{<u style="single">2</u>}<u style="single">; (xxix) 2.70 ~ 2.80mm</u>^{<u style="single">2</u>}<u style="single">; (xxx) 2.80 ~ 2.90mm</u>^{<u style="single">2</u>}<u style="single">; (xxxi) 2.90 ~ 3.00mm</u>^{<u style="single">2</u>}<u style="single">; (xxxii) 3.00 ~ 3.10mm</u>^{<u style="single">2</u>}<u style="single">; (xxxiii) 3.10 ~ 3.20mm</u>^{<u style="single">2</u>}<u style="single">; (xxxiv) 3.20 ~ 3.30mm</u>^{<u style="single">2</u>}<u style="single">; (xxxv) 3.30 ~ 3.40mm</u>^{<u style="single">2</u>}<u style="single">; (xxxvi) 3.40 ~ 3.50mm</u>^{<u style="single">2</u>}<u style="single">; (xxxvii) 3.50 ~ 3.60mm</u>^{<u style="single">2</u>}<u style="single">; (xxxviii) 3.60 ~ 3.70mm</u>^{<u style="single">2</u>}<u style="single">; (xxxix) 3.70 ~ 3.80mm</u>^{<u style="single">2</u>}<u style="single">; (xl) 3.80 ~ 3.90mm</u>^{<u style="single">2</u>}<u style="single">; And (xli) 3.90 ~ 4.00mm</u>^{<u style="single">2</u>}<u style="single">, Item 21 or 22.</u><u style="single">[Item 24]</u><u style="single"> The target is the first distance X from the ion inlet device in the first direction.</u>_{<u style="single">1</u>}<u style="single">The ion inlet device is connected to the first vacuum stage of the mass spectrometer, and the target is located at a second distance Z from the ion inlet device in the second direction.</u>_{<u style="single">1</u>}<u style="single">The second direction is orthogonal to the first direction,</u><u style="single"> (i) X</u>_{<u style="single">1</u>}<u style="single">Is selected from the group consisting of: (i) 0 ~ 1mm; (ii) 1-2mm; (iii) 2 ~ 3mm; (iv) 3 ~ 4mm; (v) 4 ~ 5mm; (vi) 5 ~ 6mm; (vii) 6 ~ 7mm; (viii) 7 ~ 8mm; (ix) 8 ~ 9mm; (x) 9 ~ 10mm; and (xi)&gt; 10mm and / or</u><u style="single"> (ii) Z</u>_{<u style="single">1</u>}<u style="single">Is selected from the group consisting of: (i) 0 ~ 1mm; (ii) 1-2mm; (iii) 2 ~ 3mm; (iv) 3 ~ 4mm; (v) 4 ~ 5mm; (vi) 5 ~ 6mm; (vii) 6 ~ 7mm; (viii) 7 ~ 8mm; (ix) 8 ~ 9mm; (x) 9 ~ 10mm; and (xi)&gt; 10mm,</u><u style="single">The room charge analyzer according to any one of items 1 to 23.</u><u style="single">[Item 25]</u><u style="single"> The target is arranged in any one of items 1 to 24 such that the flow of the analyte droplets and / or the plurality of analyte ions are deflected toward the ion inlet device of the mass spectrometer. The described mass spectrometer.</u><u style="single">[Item 26]</u><u style="single"> The mass spectrometer according to any one of items 1 to 25, wherein the target is arranged upstream of the ion inlet device of the mass spectrometer to deflect ions toward the ion inlet device.</u><u style="single">[Item 27]</u><u style="single"> The target comprises a pin having (i) a rod or (ii) a tapered cone.</u><u style="single"> The flow of the analyte droplets is provided (i) directly on the centerline of the rod or pin or (ii) towards or away from the ion inlet orifice of the mass spectrometer. Collision on the side of the rod or taper cone, configured to collide with the rod or taper cone of the pin.</u><u style="single">The mass spectrometer according to any one of items 1 to 26.</u><u style="single">[Item 28]</u><u style="single"> The mass spectrometer according to any one of items 1 to 27, wherein the ion source includes an atmospheric ionization (API) ion source.</u><u style="single">[Item 29]</u><u style="single"> The mass spectrometer according to any one of items 1-28, wherein the target comprises a stainless steel target, a metal, gold, a non-metallic substance, a semiconductor, another substance including a metal or carbide coating, an insulator or a ceramic. ..</u><u style="single">[Item 30]</u><u style="single"> The target comprises a plurality of plates such that the droplets from the atomizer cascade on the plurality of target plates, and / or the target is such that the droplets are ionized by a plurality of oblique deflections. , The mass spectrometer according to any one of items 1 to 29, which is configured to have a plurality of collision points.</u><u style="single">[Item 31]</u><u style="single"> The mass spectrometer according to any one of items 1 to 30, wherein the target comprises one or more mesh or grid targets.</u><u style="single">[Item 32]</u><u style="single"> 31. The mass spectrometer according to item 31, wherein the one or more mesh or grid targets include one or more wire mesh or grid targets.</u><u style="single">[Item 33]</u><u style="single"> The wire mesh or grid target comprises a wire having a diameter selected from the group consisting of: (i) &lt;50 μm; (ii) 50-100 μm; (iii) 100-150 μm; (iv) 150-200 μm; (v) 200-250 μm; (vi) 250-300 μm; (vii) 300-350 μm; (viii) 350-400 μm; (ix) 400-450 μm; (x) 450-500 μm; (xi) 500-550 μm; xii) 550 ~ 600 μm; (xiii) 600 ~ 650 μm; (xiv) 650 ~ 700 μm; (xv) 700 ~ 750 μm; (xvi) 750 ~ 800 μm; (xvii) 800 ~ 850 μm; (xviii) 850 ~ 900 μm; (xix) ) 900-950 μm; (xx) 950-1000 μm; and (xxi)&gt; 1 mm, mass spectrometer according to item 32.</u><u style="single">[Item 34]</u><u style="single"> The mesh or grid has a spacing selected from the group consisting of: (i) &lt;50 μm; (ii) 50-100 μm; (iii) 100-150 μm; (iv) 150-200 μm; (v) 200 ~ 250 μm; (vi) 250 ~ 300 μm; (vii) 300 ~ 350 μm; (viii) 350 ~ 400 μm; (ix) 400 ~ 450 μm; (x) 450 ~ 500 μm; (xi) 500 ~ 550 μm; (xii) 550 ~ 600 μm; (xiii) 600 ~ 650 μm; (xiv) 650 ~ 700 μm; (xv) 700 ~ 750 μm; (xvi) 750 ~ 800 μm; (xvii) 800 ~ 850 μm; (xviii) 850 ~ 900 μm; (xix) 900 ~ 950 μm (Xx) 950 ~ 1000 μm; and (xxi)&gt; 1 mm. The mass spectrometer according to item 31, 32 or 33.</u><u style="single">[Item 35]</u><u style="single"> The one or more mesh or grid targets are either (i) substantially perpendicular to the spray axis of the one or more sprayers or (ii) 90 relative to the spray axis of the one or more sprayers. The mass spectrometer according to any one of items 31 to 34, which is configured to be arranged in a plane inclined at an angle of °.</u><u style="single">[Item 36]</u><u style="single"> The mass spectrometer according to any one of items 31 to 35, wherein the one or more mesh or grid targets provide a plurality of collision zones.</u><u style="single">[Item 37]</u><u style="single"> The mass spectrometer according to any one of items 31 to 36, wherein the one or more mesh or grid targets include a one-dimensional or two-dimensional array of crevices or openings.</u><u style="single">[Item 38]</u><u style="single"> The mass spectrometer according to any one of items 31 to 37, wherein the one or more mesh or grid targets include a plurality of layers.</u><u style="single">[Item 39]</u><u style="single"> 38. The mass spectrometer according to item 38, wherein one or more of the layers comprises a mesh or grid.</u><u style="single">[Item 40]</u><u style="single"> 38. The mass spectrometer according to item 38 or 39, wherein the plurality of layers include layers having substantially the same or substantially different mesh sizes.</u><u style="single">[Item 41]</u><u style="single"> The mass spectrometer according to any one of items 1 to 40, further comprising a vibrating device arranged and adapted to vibrate the target.</u><u style="single">[Item 42]</u><u style="single"> 41. The mass spectrometer according to item 41, wherein the target is arranged and adapted to vibrate such that the size of the resulting second droplet is reduced through surface collapse.</u><u style="single">[Item 43]</u><u style="single"> The mass spectrometer according to item 41 or 42, wherein the vibration source includes a piezoelectric vibration source.</u><u style="single">[Item 44]</u><u style="single"> The vibration source is arranged and adapted to vibrate the target at a frequency selected from the group consisting of: (i) &lt;1kHz; (ii) 1-2kHz; (iii) 2-3kHz; (iv) 3 ~ 4kHz; (v) 4 ~ 5kHz; (vi) 5 ~ 6kHz; (vii) 6 ~ 7kHz; (viii) 7 ~ 8kHz; (ix) 8 ~ 9kHz; (x) 9 ~ 10kHz; ( xi) 10 ~ 11kHz; (xii) 11 ~ 12kHz; (xiii) 12 ~ 13kHz; (xiv) 13 ~ 14kHz; (xv) 14 ~ 15kHz; (xvi) 15 ~ 16kHz; (xvii) 16 ~ 17kHz; (xviii) ) 17-18kHz; (xix) 18-19kHz; (xx) 19-20kHz; and (xxi)&gt; 20kHz, the mass spectrometer according to item 41, 42 or 43.</u><u style="single">[Item 45]</u><u style="single"> The mass spectrometer according to any one of items 1-44, further comprising a first apparatus configured and adapted to rotate and / or translate the target.</u><u style="single">[Item 46]</u><u style="single"> The mass spectrometer according to item 45, wherein the target comprises a pin or rod.</u><u style="single">[Item 47]</u><u style="single"> The target has a first central longitudinal axis, the first device is configured and adapted to rotate the target around a second axis, and the second axis is the second axis. The mass spectrometer according to item 45 or 46, which is displaced or offset from one axis.</u><u style="single">[Item 48]</u><u style="single"> The mass according to item 45, 46 or 47, wherein the first device is arranged and adapted to rotate the target on or around a substantially eccentric or non-circular path in use. Analyzer.</u><u style="single">[Item 49]</u><u style="single"> The first device is configured and adapted to rotate the target at the following speeds: (i) &lt;1rev / s; (ii) 1-2rev / s; (iii) 2-3rev / s ; (iv) 3 ~ 4rev / s; (v) 4 ~ 5rev / s; (vi) 5 ~ 6rev / s; (vii) 6 ~ 7rev / s; (viii) 7 ~ 8rev / s; (ix) 8 ~ 9rev / s; (x) 9 ~ 10rev / s; (xi)&gt; 10rev / s; (xii) &lt;1rpm; (xiii) 1 ~ 5rpm; (xiv) 5 ~ 10rpm; (xv) 10 ~ 15rpm; ( xvi) 15 ~ 20rpm; (xvii) 20 ~ 25rpm; (xviii) 25 ~ 30rpm; (xix) 30 ~ 35rpm; (xx) 35 ~ 40rpm; (xxi) 40 ~ 45rpm; (xxii) 45 ~ 50rpm; (xxiii) ) 50 ~ 60rpm; (xxiv) 60 ~ 70rpm: (xxv) 70 ~ 80rpm; (xxvi) 80 ~ 90rpm; (xxvii) 90 ~ 100rpm; (xxviii) 100 ~ 150rpm; (xxix) 150 ~ 200rpm; (xxx) 200-250 rpm; and (xxxi)&gt; 250 rpm, mass analyzer according to any one of items 45-48.</u><u style="single">[Item 50]</u><u style="single"> The mass spectrometer according to any one of items 45 to 49, wherein the first apparatus is arranged and adapted so as to rotate the target substantially continuously.</u><u style="single">[Item 51]</u><u style="single"> The first device is configured and adapted to rotate the target substantially continuously over at least a period of time T, where T is selected from the group consisting of: (i) &lt;1s; (ii). ) 1 ~ 5s; (iii) 5 ~ 10s; (iv) 10 ~ 15s; (v) 15 ~ 20s; (vi) 20 ~ 25s; (vii) 25 ~ 30s; (viii) 30 ~ 35s; (ix) 35 ~ 40s; (x) 40 ~ 45s; (xi) 45 ~ 50s; (xii) 50 ~ 55s; (xiii) 55 ~ 60s; and (xiv)&gt; 60s, described in any one of items 45 ~ 50 Mass spectrometer.</u><u style="single">[Item 52]</u><u style="single"> The mass according to any one of items 1 to 51, wherein the mass spectrometer includes a control system, which is configured and adapted to monitor the analyte signal as a function of the position of the target. Analyzer.</u><u style="single">[Item 53]</u><u style="single"> The control system is configured and adapted to rotate the device to the desired position and / or translate the target so that the analyte ion signal is optimized or the analyte ion intensity is increased. The mass spectrometer according to item 52, which is controlled.</u><u style="single">[Item 54]</u><u style="single"> The control system is configured and adapted to rotate and / or translate the target between a plurality of desired positions, thereby varying or controlling the intensity of the analyte ion, item 52 or 53. The mass spectrometer described in.</u><u style="single">[Item 55]</u><u style="single"> It s a method of mass spectrometry.</u><u style="single"> To provide a separator configured and adapted to release the eluent over time, said separator is (i) a capillary electrophoresis (CE) separator, (ii) capillary. Includes an electronic chromatography (CEC) separator, (iii) a substantially rigid ceramic-based multilayer microfluidic substrate (ceramic tile) separator or (iv) a supercritical fluid chromatography separator. ,</u><u style="single"> Providing a target and</u><u style="single"> By spraying the eluate released from the separator, the flow of the analyte droplets is directed and collided with the target to ionize the analyte to form a plurality of analyte ions. That and, including, methods.</u>