WO2005119736A1

WO2005119736A1 - Electrospray ion generation with stimulation

Info

Publication number: WO2005119736A1
Application number: PCT/EP2004/051024
Authority: WO
Inventors: Uwe Effelsberg
Original assignee: Agilent Technologies, Inc.
Priority date: 2004-06-04
Filing date: 2004-06-04
Publication date: 2005-12-15

Abstract

An electrospray ionization device comprises a tip of a capillary tube (1) arranged in a chamber (5) and being adopted for injecting a sample solution into the chamber (5). A high voltage source (16) adopted for generating a first electrical field between a tip (4) of the capillary tube (1) and a first area of said chamber (5) is provided. The device comprises a generator (15) adopted for generating an alternating signal with a frequency of at least 10 kHz. The generator (15) is coupled to the capillary tube (1) for stimulating the generation of ion droplets out of the injected sample solution in response to generated pulses.

Description

DESCRIPTION ELECTROSPRAY ION GENERATION WITH STIMULATION

BACKGROUND ART

[0001] The present invention relates to generation of electrospray ion droplets.

[0002] Electrospray ionization is a technique for dissolving of charged biomolecules into a gaseous phase. The method is often used for mass spectrometry and especially for time of flight (TOF) mass spectrometers. The electron spray ionization process is much more sensitive and comprises a higher ion creation efficiency in the range of 0.01 to 0.1 compared to normal ionization processes in the range of 10^"4. In a typical example, enzymes are employed to digest proteins into peptide segments. These segments are separated, for example by a liquid chromatography process and electrosprayed into a mass spectrometer. The results of the mass spectrometer will give information about the charge to mass ratio of the protein and the peptides sprayed into the spectrometer.

[0003] Some reviews for the fundamental physics of the electrospray ionization process can be found in Bruins A.P. "Mechanistic Aspects of Electrospray Ionization", Journal of Chromatography A, vol.794, pp.345 to 347, 1998 or Chech et al., "Practical Implications of Some Recent Studies in Electrospray Ionization Fundamentals", Mass Spectrometry Reviews, vol. 20, pp. 362 to 387, 2001.

[0004] The electrospray ionization process produces a cloud of ions in the gaseous phase. For a better control of ion generation the solution to be analyzed is pumped at a slow flow rate through a small capillary tube. Depending on the flow rate one speaks of μESI or even n(nano)ESI. The capillary tube is placed within a high electric field, normally generated by applying a first potential to the capillary tip and a second potential to a member interface of the mass spectrometer having an orifice and a transfer capillary for further analysis build in it. When the sample to be analyzed leaves the capillary tip the charged ions within the sample become partly separated. [0005] For example, negative charged ions within the sample are concentrated on the walls due to a positive potential of the capillary and partly neutralized by the charges applied. Positive ions of the sample are concentrated on the surface of the solution outside the capillary tip. Depending on the electric field, the combined electrostatic and hydrodynamic forces of the liquid are balanced by surface tension of the solution, thereby creating the so-called Taylor cone. At a given electric field, depending also on the flow rate of the sample solution, small charged droplets become separated at the top of the Taylor cone and are accelerated within the electric field. The separation of charged ions cause an ion current usable, for example, in time of flight mass spectrometers. However, the applied electric field generates droplets of large distribution in size and charge. Therefore results in a time of flight mass spectrometer might become unstable.

[0006] Attempts have been made to produce a stable distribution of ions. An example of such an electrospray ionization mass analysis apparatus is given in the US application US 2003/0183757.

[0007] Another attempt is found in US provisional application 60/543,542. In the application an electrospray ion generation device is disclosed, the device comprising a closed loop. The loop couples an AC stimulation of the electric field onto the droplet generation frequency. The generation frequency therefore becomes more stable and measurement sensitivity of a time of flight mass spectrometer is increased.

DISCLOSURE OF THE INVENTION

[0008] It is an object of the invention to provide an improved electrospray ionization for analysis. This object is solved by the independent claims. Preferred embodiments of the invention are subjects of the dependent claims.

[0009] According to the invention an electrospray ionization device comprises a capillary tube arranged in a chamber and adopted for injecting a sample solution into the chamber. It further comprises a high voltage source adopted for generating an electric field between the tip of the capillary and an area of said chamber, thereby generating a spray of ion flow of the injected sample solution. To stabilize the ion generation and create a well-defined mass and size distribution of the spray flow, a generator is provided, which is adopted for generating an alternating signal with a frequency of at least 10 kHz. The generator is coupled to the capillary tube or the tip for a stimulation of ion droplets generation out of the injected sample solution in response to the generated signals.

[00010] It was recognized that by applying a signal with a frequency of at least 10 kHz and coupling the generator to the capillary tube, small charged droplets are separated of the injected sample solution at the top of the capillary tip. Hence the generation of droplets is directly coupled the stimulation frequency. Dependent on the frequency and the flow rate of the solution, the size distribution can be specified and remains relatively stable over time. Additionally one can use different sample solution comprising different molecules to be analyzed without the need of new adjustment. The generator is coupled so that the sample solution at the top of the capillary tube is stimulated to generate charged droplets out of the injected sample solution.

[00011] In a preferred embodiment of the invention, the electrical field comprisesan at least temporary static component and is generated by the high voltage source is applied between the capillary tip and a sidewall of the chamber. Thatsidewall is having an orifice and preferably a transfer capillary adopted for receiving at least part of the generated spray ion flow for further analysis. In other words, the generated ion droplets with a specific size distribution are accelerated by the electric field and enter the mass spectrometer through the orifice in the sidewall of the chamber.

[00012] In an embodiment of the invention, the generator is adopted for generating an AC voltage pulse. The AC voltage pulse is being applied to the tip of the capillary. Alternatively the generator is adopted for superimposing an alternating electric field onto the electric field being generated by the high voltage source. In this embodiment of the invention the droplets are generated by ripping them off the injected sample solution at the top of the capillary tip through the alternating electric field. The static electric field of the high voltage source is modulated with an alternating signal. Thereby the droplet formation during the electrospray ionization process is coupled and forced to the frequency of the generated alternating signal. The size of the electrospray ionization droplets can be controlled and is not dependent on changes of solvent composition during analysis.

[00013] In an embodiment of the invention the alternating signal comprises a pulsating signal, pulses or a sine wave.

[00014] In another embodiment of the invention, the generator is adopted for generating a mechanical vibration of the tip of the capillary tube. This mechanical vibration results in an oscillation of the capillary tube ripping small droplets off the tip of the capillary tube, which are then accelerated by the electrical field. In a further embodiment the generator comprises a piezoelectric crystal coupled to the capillary tube. The crystal is adopted for being stimulated by an AC voltage. Due to the stimulation of the AC voltage the piezoelectric crystal changes its dimension, thereby generating a mechanical vibration of the capillary tube. In a preferred embodiment the piezoelectric crystal is arranged with one surface on a sidewall of the capillary near the tip. Preferably the piezoelectric crystal comprises BaTiO3, Li2SO4, or a ferroelectric with Perowskit structure, or a polymer having a crystallite structure like polyvinylchloride or derivates, polyidenfluoride (PDF) or polyvinylidenfluoride (PVDF).

[00015] In yet another embodiment of the invention, the generator is adopted for generating acoustic wave pulses across the tip of the capillary tube. Due to the acoustic pressure generated charged sample solutions are separated from the tip. Generating charged droplets using acoustic pulses results i n a very stable and specific charge and size distribution. In this embodiment of the invention the generator comprises a loudspeaker and a horn respectively, adopted for generating a sound pulse. Preferably the loudspeaker or the horn is arranged within an angle of 80° to 100° compared to the tip orifice of the capillary tube.

[00016] It is also possible to generate acoustic pulses onto a sidewall of the capillary tube, thereby causing vibrations of the capillary tube. [00017] In a further embodiment of the invention, the tip of the capillary tube is arranged within an angle of 80° to 100° compared to the orifice of the sidewall. Thus in this embodiment, the tip of the capillary tube and the capillary tube are arranged almost perpendicular to an orifice of the sidewall and the inlet area of the mass spectrometer.

[00018] In an embodiment of the invention, the sample solution flow through the capillary tube into the chamber is in the range of 1 Nanoliter per minute to 10 Microliter per minute and is preferably 100 Nanoliter per minute. The generator is adopted for generating pulses with a frequency within the range of at least 10 kHz up to 500 kHz. Depending on the dimension of the capillary tube and the analysis instrument, other flow rates through the capillary tube as well as other pulse frequencies can also be used. In yet another embodiment of the invention, the electric field applied between the tip and the sidewall of the chamber lies within the range of 10⁶ volt per meter to 10⁷ volt per meter or a potential difference of 1 kV to 5 kV.

[00019] According to an embodiment of the invention, a static electric field is being generated between a tip of the capillary tube and a sidewall of the chamber. Then the sample solution is being injected into the capillary tube, forming a so-called Taylor cone at the top of the capillary tube. The Taylor cone is formed due to a separation of charged ions within the solution, resulting in a high concentration of charged molecules at the top. Then charged droplets of sample solution are created by separating sample solution from a tip of the capillary tube using a frequency of at least 10 kHz. The solution or the Taylor cone on the top of the tip is thereby stimulated with a frequency of at least 10 kHz. The size of the charged droplets generated by the separation is dependent on the frequency and the flow rate of the sample solution through the capillary tube. However, if a fixed flow rate is chosen changing the frequency of the charged droplets separation will result in different size and mass distribution of the charged droplets. Therefore it is possible to generate a stable flow of droplets in an electrospray ionization process by carefully choosing the frequency.

[00020] In an embodiment of the invention, the droplets are generated by superimposing an alternating electric field onto the static electric field, thereby pulling or ripping droplets of sample solution off the tip of the capillary tube. In yet another embodiment the droplets are generated by oscillating the capillary tube mechanically. In an embodiment this is done by applying a pulse voltage onto a piezoelectric crystal, which is connected to the capillary tube. Due to the pulse voltage the piezoelectric crystal changes its dimensions resulting in an oscillation of the capillary tube. In another embodiment of the invention the droplets are generated by applying sound and/or acoustic pulse(s) onto the tip of the capillary tube. Charged droplets are then separated from the rest of the sample solution due to the acoustic pressure. BRIEF DESCRIPTION OF DRAWINGS

[00021] Other objects and many of the attendant advantages of embodiments of the present invention will be readily appreciated and be better understood by reference to the following description of preferred embodiments. The accompanied drawings are for illustration purposes only and do not limit the scope of the invention. Features that are substantially or functionally equal or similar will be referred to with the same reference signs.

[00022] Figure 1 shows a first embodiment of the present invention.

[00023] Figure 2 shows a second embodiment of the present invention.

[00024] Figure 3 shows a capillary tube in a chamber according to a third embodiment of the present invention.

[00025] Figure 4 shows a capillary tube in a chamber according to a fourth embodiment of the present invention.

[00026] Figure 5 shows a capillary tube in the chamber according to a fifth embodiment of the present invention.

[00027] Figure 6 shows a detailed view of the capillary tip according to an embodiment of the present invention. [00028] Figure 1 shows an overall configuration of an electrospray ionization mass spectrometer. The mass spectrometer itself includes different embodiments. In this specific non-limiting embodiment, it is adopted as a quadrupole mass spectrometer. Such a spectrometer comprises four parallel metallic rods 13 arranged on the edges of a virtual square 13. The two opposite metallic rods are connected together, having the same potential and then coupled to the AC generator 13A. An AC voltage is applied to the metallic rod 13. Dependent on the frequency and the amplitude of the applied AC voltage, ions comprising a specific charge to mass ratio are able to pass through the area, while other ions with different charge to mass ratios are filtered. Ions passed through the quadrupoles are flying through the orifice of screen 12 and finally detected by the detector 11. The advantage of a quadrupole mass spectrometer lies in the insensitivity of charge and mass distribution of the generated droplets.

[00029] The embodiment of the present invention according to figure 1 further comprises a chamber 5 comprising a first sidewall 7. The sidewall 7 comprises a transfer capillary 6 arranged opposite to a capillary tube 1. Furthermore the sidewall 7 comprises a metal coating layer connected to the mass potential.

[00030] The capillary tube 1 comprises a metal-coated tip 4, which is also connected to a first high voltage generator 16 and a second AC voltage generator 15. Both generators are connected to mass potential. The connection between the generators 15 and 16 respectively and the metal coated tip 4 can be on the outer coating, but also on an inner coating, if the tip comprises a small inner metal coating layer.

[00031] The metal-coated layer might comprise preferable a non-oxidizing material, for example Au, Ag, Pt or the like. Other material, which are inert to the solvent or the specimen are also possible, for example Ti, W, or even stainless steel. The thickness of the layer might also vary. It might be thicker on the top of the tip due to the electrostatic forces.

[00032] The capillary tube 1 together with its tip 4 is arranged within a second tube 2 having an orifice 3. The AC voltage generator 15 connected to the tip 4 is also connected to a detector system 14, which is coupled to the detector 11. The system 14 is adopted for retrieving the AC voltage signal as well as a detector signal from the detector 11. It further comprises means for display and further signal processing. Generators as well as the detector system is controlled by a computer and more specifically by a software program executed on the computer. A user can select parameters in the software, while the software controls flow rate, stimulation frequency and amplitude for example in order to optimize results.

[00033] If a sample solution is injected into capillary 1, a droplet will be formed on the top of tip 4. If no electric field is applied, the droplet contains positive and negative charged ions. As soon as an electric field is applied between the metallic tip 4 and the surface of the sidewall 7, the ions within the droplet at the top of the tip 4 become separated. In this specific case negative charged ions are concentrated onto the sidewall of the tip 4 and are partly reduced by the positive charge applied to the tip by the high voltage generator 16. At the same time, positive charged ions in the droplets are drawn along the created electric field towards the sidewall 7.

[00034] The balance between the electric field and the surface tension of the sample solution results in a cone-like structure on the top of the tip 4, called a Tailor cone. Depending on the electric field and the flow rate of the sample solution, the Tailor cone is not stable and positive charged droplets are separated from the solution. At this point the cone starts to emit a spray of ions.

[00035] The size and mass distribution of the droplets can be controlled by applying an AC voltage thereby generating an alternating electric field and superimposing the alternating electric field onto the static electric field between the tip 4 and the sidewall 7. The alternating electric field is generated by the AC voltage generator 15 adopted for generating pulses in the range of 400 V. The sudden increase of the electric field stimulates the ripping of droplets off the formed Tailor cone in response to the frequency of the now alternating electric field. The generation of droplets therefore becomes coupled to the applied AC voltage. The size and/or mass distribution of the droplets can be controlled by the pulse frequency as well as by the flow rate of the sample solution through the capillary tube. [00036] At the same time nitrogen N₂ or a similar inert gas is inserted between the capillary tube 1 and the tube 2. The nitrogen is used for drying the generated droplets by evaporating the solvent. The loss of solvent molecules by evaporation results in a disintegration of the smaller charges droplets and creation of so-called microdroplets. Due to the increase in the coulomb repulsion of charged particles in the decreasing droplet, the droplet might evaporate charged particles or divide into smaller droplets. This process is continued until a gaseous phase of ions is generated. The ions are accelerated by the electric field and passing through the transfer capillary 6 the skimmer 10 and are then separated according to their charge to mass ratio in the quadrupole mass spectrometer 13 and detected in the detector 11.

[00037] A slightly different arrangement of an embodiment of the present invention can be seen in figure 2. The capillary tube 1 together with its gold-coated tip 4 is arranged almost perpendicular to the orifice of the transfer capillary 6. Additionally a time or flight mass spectrometer is used instead of a quadruple mass spectrometer. A time of flight mass spectrometer (TOF-mass spectrometer) is a pulsed working spectrometer. The charged particles to be analyzed are accelerated by the applied voltage U and detected after passing through the transfer capillary 6. The flight time t through the capillary 6 comprising the length s can be measured. The charge to mass ratio will be: e/m = s²/2Ut²

[00038] In this embodiment of the invention the tip 4 of the capillary tube 1 is connected to a high voltage source 16 as well as to a pulse generator 15 via a capacitor 17. The capacitor 17 is used for de-coupling the DC voltage generated by the high voltage source 16. The sidewall 7 coated with a metallic layer is also connected to the high voltage source 16. Applying a DC voltage between the tip 4 and the sidewall 7 results in an electric field accelerating positive charged ions from the tip 4 along the electrode towards the transfer capillary 6. The sidewall 7 also comprises two orifices for inserting nitrogen into the chamber 5.

[00039] A third embodiment of the present invention can be seen in figure 3. The orifice 4A of the capillary tube 1 is arranged opposite to the transfer capillary 6. In this embodiment of the invention the tip 4 is coated with a metallic layer and connected to a high voltage source for applying a static electric field between the tip 4 and the sidewall 7. Furthermore an auxiliary electrode 20 is applied and arranged around the capillary 1. When a static electric field is being applied between the tip 4 and the sidewall 7 it becomes normally divergent resulting in a very low ion density in the transfer capillary 6. The sensitivity of a mass spectrometer therefore decreases. The arrangement of the auxiliary electrode 20 can be used to focus the electric field and to reduce the divergence to increase the ion density at the orifice of sidewall 7. The arrangement of the auxiliary electrode 20 and the metal capil lary 1 can also be seen in the United States patent US 6,462,337 by Lee et al., which is incorporated herein by reference.

[00040] In this embodiment of the invention the droplets are generated via mechanical vibration of the capillary tube 1. After a Tailor cone of positive charged ions is formed at the top 4A of the tip 4 positive droplets are ripped off the Tailor cone by vibrating or sudden movement of the capillary tube 1. This sudden movement is performed by a piezoelectric crystal 22 arranged on a sidewall of the capillary tube 1 and connected to a rigid carrier 21. The piezoelectric effect has been found in many isolating crystals, not comprising a symmetric center. Their crystal structures are characterized by one or more polar axis. Due to mechanical deformation an electrical dipole moment is created resulting in a charge on the surface of the crystal. On the other hand by applying an electrical alternating field onto a piezoelectric crystal dipole moments within the crystal are created, resulting in a deformation of the crystal structure. Typical piezoelectric crystals are LiTaO₃, LiNBO₃, some ceramic materials but also plastics like polyvinylhydeneflouride PVDF, polyvinylchloride PVC or PVF.

[00041] The piezoelectric crystal arranged on the sidewall of the capil lary tube 1 is connected to an AC voltage generator. By applying an AC voltage with a frequency of at least 10 kHz or even more the capillary tube 1 starts to oscillate. The inertia of the Taylor cone on top 4A of the tip 4 compared to the movement of the capillary tube 1 will rip off the charged droplet. [00042] This process can be seen in detail in figure 6. A Tailor cone 4A is formed at the top of the tip 4 of capillary tube 1. The Tailor cone 4A comprises a high concentration of positive charged ions. Negative charged ions are concentrated on the sidewall of the capillary tube 1 and are partly oxidized by positive charges. The capillary tube 1 is connected to the high voltage source 16 also coupled via a current detector to the sidewall 7. The sidewall 7 therefore is negatively charged. As one can see the capillary tube 1 is moved with a high frequency along the z-axis. Due to this sudden movement, droplets of charged positive ions at the top of the Tailor cone are ripped off their remaining fluid and accelerated in the static electric field between the tip 4 and the sidewall 7. Solvent is evaporated and positive charged ions are evaporated from the remaining droplets or the droplets are breaking up into smaller microdroplets. Due to the focusing effect of the auxiliary electrode not shown herein, a high density of single charged molecules is passing through the orifice into the transfer capillary 6.

[00043] The creation of a droplet causes a current change, detectable by the current detector A. The creation of the droplet is coupled directly to the frequency of a vibration of the capillary tube 1. In particular the size of the droplet is dependent on the flow rate as well as on the amplitude and the frequency of the vibration. Increasing the flow rate results in the creation of bigger droplets. Increasing the frequency and amplitude of the vibration will reduce the size of the droplets.

[00044] A similar embodiment can also be seen in figure 4. The capillary tube 1 comprises an angle of 90 degree. The piezoelectric crystal 22 is connected to the capillary tube at the edge of the capillary tube 1. By AC stimulation of the crystal 22 the capillary tube is moved towards the orifice 6 on the sidewall 7 and in the opposite direction. The movement causes droplets to be ripped off the Taylor cone on top of tip 4.

[00045] A further embodiment of the present invention is shown in figure 5. In this specific embodiment the invention also comprises a time or flight mass spectrometer with a transfer capillary 6 and a mass spectrometer detector not shown herein. The orifice of the capillary 1 is arranged almost perpendicular to the orifice of the transfer capillary 6. In this embodiment of the invention the droplets of a specific size and mass distribution are generated by an acoustic pulse created by a loudspeaker 30. The loudspeaker or horn 30 is arranged next to the tip 4 of the surface capillary 1. The loudspeaker 30 generates a supersonic acoustic pulse with a frequency of at least 10 kHz using a generator 15. The acoustic pressure will rip off a small droplet at the top of the Tailor cone at the tip 4. Once again the size of the droplet is controlled by the frequency of the amplitude of the acoustic pulse as well as the flow rate of the sample solution through the capillary 1.

[00046] The static electric field applied in all embodiments of the invention is lower than the threshold voltage, at which normal electrospray ionization begins. For example the voltage of the static electrode might be in the range of 1 to 5 kV and preferably 2.5 kV. If an alternating electric field with a frequency of at least 10 kHz is applied to the static electric field, the amplitude of the AC voltage causing the alternating electric field might be in the range of 200 to 600 Volts and preferably 500 Volts. The sum of both field i ncreases over the threshold value at which the generation of droplets begins. The stimulation frequency might be at least 10 kHz, but can also be in the range between 10 kHz and 500 kHz. At 500 kHz stimulation an almost continuous flow of droplets is created. In this embodiment the flow rate might be increased, if a bigger droplet size is needed.

[00047] The main aspect of the invention of creating droplets of a specific size by stimulating the droplet separation from the Tailor cone can be used in different kinds of mass spectrometers. Next to the quadrupole mass spectrometer shown in figure 1 and the time or flight mass spectrometer shown in figure 2, magnetic field devices or combinations of mass spectrometers can also be used. The present invention is not limited to the various embodiments and examples shown herein. Other methods for stimulating the creation of droplets and thereby determining that mass and charge distribution can be used within the scope of protection.

Claims

1. An electrospray ionization device comprising: - a tip (4) of a capillary tube (1) arranged in a chamber (5) and being adopted for injecting a sample solution into the chamber (5); - an high voltage source (16) adopted for generating an first electric field between the tip (4) of the capillary tube (1) and a first area of said chamber, thereby generating a spray ion flow of the injected sample solution; - a generator (15) adopted for generating an alternating signal with a frequency of at least 10 kHz, the generator (15) being coupled to the capillary tube (1 ) for stimulating the generation of ion droplets out of the injected sample solution in response to generated pulses.

2. The electrospray ionization device of claim 1 or any one of the above claims, wherein the generator (15) is coupled to the tip of the capillary tube (1).

3. The electrospray ionization device of claim 1 or any one of the above claims, wherein the first electric field comprises an at least temporary static component.

4. The electrospray ionization device of claim 1 or any one of the above claims, wherein the generator (15) is adopted for generating pulses.

5. The electrospray ionization device of claim 1 or any one of the above claims, wherein the first area comprises a sidewall (7) of the chamber (5) having an orifice adopted for receiving at least part of the generated spray ion flow for further analysis.

6. The electrospray ionization device of claim 1 or any one of the above claims, wherein the orifice is connected to an electrostatic neutral transfer capillary (6).

7. The electrospray ionization device of claim 1 or any one of the above claims, wherein the generator (15) is adopted for generating an alternating voltage signal, the alternating voltage signal being applied to the tip (4) of the capillary (1).

8. The electrospray ionization device of claim 1 or any one of the above claims, wherein the generator (15) is adopted for superimposing an alternating electric field onto the electric field being generated by the high voltage source (16).

9. The electrospray ionization device of claim 8 or any one of the above claims, wherein the alternating electric field and the electric field is formed between the tip (4) and a sidewall (7) of the chamber (5) comprising the orifice as to direct the spray ion flow to the orifice.

10. The electrospray ionization device of claim 1 or any one of the above claims, further comprising an auxiliary electrode (20) adopted for focusing the electrical field as to decrease any divergence of the beam of spray ions on the way to the orifice.

11. The electrospray ionization device of claim 1 or any one of the above claims, wherein the generator (15) is adopted for generating a mechanical vibration of the tip (4) of the capillary tube (1).

12. The electrospray ionization device of claim 1 or any one of the above claims, wherein the generator (15) comprises a piezoelectric crystal (22) coupled to the capillary tube (1 ), the crystal (22) adopted for being stimulated by an AC- voltage, thereby generating a mechanical vibration of the capillary tube (1).

13. The electrospray ionization device of claim 12 or any one of the above claims, wherein the piezoelectric crystal (22) is arranged with one surface on a sidewall of the capillary tube (1) near the tip (4).

14. The electrospray ionization device of claim 12 or any one of the above claims, wherein the piezoelectric crystal (22) comprises BaTiO3, Li2SO4, or a ferroelectric with Perowskit structure, or a polymer having a crystallite structure like PVC, PDF or PVDF.

15. The electrospray ionization device of claim 1 or any one of the above claims, wherein the generator (15) is adopted for generating acoustic wave pulses across the tip (4) of the capillary tube (1 ).

16. The electrospray ionization device of claim 1 or any one of the above claims, wherein the generator (15) comprises a loudspeaker (30) or comprises a horn adopted for generating sound wave pulses with an angle of 80 to 100 degree to the tip orifice of the capillary tube (1 ).

17. The electrospray ionization device of claim 1 or any one of the above claims, wherein the generator (15) is adopted for generating pulses with a frequency in the range of at least 10 kHz up to 500 kHz.

18. The electrospray ionization device of claim 1 or any one of the above claims, wherein the tip (4) of the capillary tube (1) comprises a metal coating layer, the metal coating layer coupled to the high voltage source (16).

19. The electrospray ionization device of claim 5 or any one of the above claims, wherein the tip (4) of the capillary tube (1 ) is arranged with an angle of 80 to 100 degree to the orifice of the sidewall (7).

20. The electrospray ionization device of claim 1 or any one of the above claims, wherein a value of a sample solution flow through the capillary tube (1 ) into the chamber (5) is in the range of 1 nl/min to 10 μl/min and preferably 100 nl/min.

21. The electrospray ionization device of claim 1 or any one of the above claims, wherein the high voltage source (16) is adopted for applying an electrical field in the range of 10^Λ6 V/m to 10^Λ7 V/m between the tip (4) and the chamber area.

22. The electrospray ionization device of claim 1 or any one of the above claims, wherein the high voltage source (16) is adopted for applying a potential difference of 1 kV to 5 kV between the tip (4) and the area of the chamber (5).

23. The electrospray ionization mass analysis device of claim 1 or any one of the above claims, wherein the generator (15) is adopted for generating an AC-voltage in the range of 200 V to 600 V.

24. Method for providing ions of a sample solution for analysis, the method comprising the steps of: - generating a first electric field between a tip (4) of a capillary tube (1) and area of a chamber; - injecting a sample solution into the capillary tube (1) and into the tip (4); - generating charged droplets by separating sample solution from the tip (4) with a frequency of at least 10 kHz; - evaporating solvent of the droplets thereby generating a cloud of sample ions.

25. The method of claim 24 or any one of the above claims, wherein generating the first electric field comprises the step of generating an at least temporary static electric field.

26. The method of claim 24 or any one of the above claims, wherein the charged droplets are generated by superimposing an alternating electric field onto the electric field thereby pulling droplets of sample solution off the tip (4).

27. The method of claim 24 or any one of the above claims, wherein the charged droplets are generated by oscillating the capillary tube (1 ) mechanically, thereby ripping the droplets off the sample solution on the top of the tip (4).

28. The method of claim 24 or any one of the above claims, wherein the droplets are generated by applying an alternating voltage signal onto a piezoelectric crystal (22) connected to the capillary tube (1 ).

29. The method of claim 24 or any one of the above claims, wherein the charged droplets are generated by applying acoustic pulses onto the tip of the capillary.

30. The method of claim 24 or any one of the above claims, wherein the generation of droplets is coupled to a stimulation of the sample solution.

31. Method for providing ions of a sample solution for analysis in an electrospray ionization device, wherein an electric field is generated between a tip (4) of a capillary tube (1 ) and area of a chamber and a sample solution is injected into the capillary tube (1) and into the tip (4), the method comprising the steps of: - applying an AC-signal with a frequency of at least 10 kHz for generating charged droplets by separating sample solution from the tip (4) in order to evaporate solvent of the droplets thereby generating a cloud of sample ions.

32. Method of claim 31 or any of the above claims wherein applying an AC-signal comprises the steps of: - controlling a generator for AC-signal generation; - controlling the flow rate through the capillary tube.

33. A software program or product, preferably stored on a data carrier, for executing the method of claim 24 or any one of the above claims, when run on a data processing system such as a computer.