JP2010509748A - Method and apparatus for generating ions for mass spectrometry - Google Patents

Abstract

An apparatus and method for reducing contamination in a mass spectrometer system is disclosed. The system includes an ion source at a first pressure that generates ions by laser desorption / ionization and an inlet opening to a vacuum chamber at a second pressure that is lower than the first pressure of the ion source. A sample plate in the ion source supports the sample deposited thereon, and the laser is at least a portion of the sample at an angle of incidence of about 0 to about 80 degrees with respect to the center line of the first ion optic axis of the mass spectrometer. Can be configured to generate a plume. The combination of the angle of incidence of the laser pulse and the distance between the sample plate and the inlet region opening can reduce neutral contaminants in the plume drawn into the inlet opening.

Description

  The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described in any way.

(Cross-reference to related applications)
This application claims the benefit of US Provisional Patent Application No. 60 / 779,818, filed Mar. 7, 2006, which is hereby incorporated by reference.

(Field)
Applicants' teachings relate to a method and apparatus for generating ions by laser desorption / ionization for analysis by a mass spectrometer.

  Mass spectrometry is a commonly used analytical method that identifies molecules in a compound based on the detection of the mass to charge ratio of ions generated from charged molecules. There are a number of ways to ionize molecules. One such method is laser desorption / ionization.

  An example of a laser desorption / ionization technique is matrix-assisted laser desorption / ionization (MALDI). In MALDI, a sample is typically mixed with an ultraviolet absorbing compound known as a MALDI matrix, deposited on the surface, and ionized with a laser pulse. The energy of the laser is absorbed by the matrix molecules and transmitted to the sample molecules, which are evaporated and ionized. An ion plume is generated and the ions are then analyzed by a mass spectrometer.

  In addition, there may be contaminants in the plume, such as matrix and neutral molecules, along with ions. These contaminants may enter the mass spectrometer as well, stick to the surface, and collide to form deposits. These deposits can accumulate over time and can degrade the performance of the mass spectrometer system. For example, deposits on the electrodes can distort the potential, thereby reducing system sensitivity and resolution. In addition, frequent cleaning is required to remove contaminants, which may result in reduced system operability, which is inefficient and problematic, especially for high throughput applications. .

  In accordance with one aspect of Applicant's teachings, ions are generated by laser desorption / ionization for analysis by a mass spectrometer having an inlet opening to a vacuum chamber at a second pressure lower than the first pressure of the ion source. An ion source at a first pressure is provided. The ion source includes a surface (eg, a sample plate) for supporting a sample deposited thereon and a laser configured to generate a laser pulse that strikes at least a portion of the sample. In various embodiments, the laser pulse can have an angle of incidence of about 0 to about 80 degrees with respect to the centerline of the ion path of the mass spectrometer, referred to herein as the first ion optical axis of the mass spectrometer. For example, in various embodiments, the laser pulse strikes the sample plate at an angle greater than about 20 degrees with respect to the first ion optical axis of the mass spectrometer. In various embodiments, the normal of the sample plate can be at an angle of about 0 to about 45 degrees with respect to the first ion optical axis of the mass spectrometer. In various embodiments, the normal of the sample plate can be tilted at an angle of about 20 to about 45 degrees with respect to the first ion optical axis of the mass spectrometer. In laser desorption, a plume is generated that may contain analyte ions of sample and neutral contaminants. In a structure that separates the inlet region from the mass spectrometer, molecules enter the mass spectrometer through the inlet opening.

  The distance between the sample plate and the inlet region opening is selected to reduce neutral molecules drawn into the inlet region of the mass spectrometer by the gas flow resulting from the differential pressure between the ion source and the mass spectrometer. The In various embodiments, as the plume moves away from the sample plate surface, the plume center is directed substantially away from the inlet region and an electric field is applied to draw analyte ions into the inlet region of the mass spectrometer. In various embodiments, the combination of the angle of incidence of the laser pulse and the distance between the sample plate and the entrance region opening is such that when the plume is separated from the sample plate surface, the plume is substantially from the entrance region of the mass spectrometer. Separated and configured to prevent neutral contaminants from being drawn into the mass spectrometer. The gas resistance resulting from the differential pressure between the ion source and the mass spectrometer is very low so that it does not draw a significant proportion of neutral contaminants through the inlet opening. The distance between the sample plate and the inlet opening is selected so as to have the effect of being removed. In various embodiments, the laser pulse strikes the sample plate at an angle of incidence greater than about 20 degrees with respect to the first ion optical axis of the mass spectrometer. In various embodiments, an electric field is applied to draw analyte ions into the entrance region of the mass spectrometer.

  In another aspect, a system is provided for generating analyte ions by laser desorption / ionization of a sample for mass spectrometry. The system includes a mass having an ion source at a first pressure for generating analyte ions and an inlet opening for receiving analyte ions in a vacuum chamber at a second pressure lower than the first pressure of the ion source. With an analyzer. The ion source includes a surface (eg, a sample plate) for supporting a sample deposited thereon and a laser configured to generate a laser pulse that strikes at least a portion of the sample. In various embodiments, the normal of the sample plate can be positioned at an angle of about 0 to about 45 degrees with respect to the first ion optical axis of the mass spectrometer, and the laser pulse is the first of the mass spectrometer. The incident angle can be about 0 to about 80 degrees with respect to the center line of the ion optical axis. In various embodiments, the normal of the sample plate can be tilted at an angle of about 20 to about 45 degrees with respect to the first ion optical axis of the mass spectrometer, and the laser pulse can be An incident angle of about 0 to about 80 degrees can be taken with respect to the centerline of one ion optical axis. In laser desorption, a plume is generated that may contain analyte ions of sample and neutral contaminants. Such gas resistance is significant so that the gas resistance resulting from the differential pressure between the ion source and the mass spectrometer does not draw a significant proportion of neutral contaminants through the inlet opening. The distance between the sample plate and the inlet opening is chosen to have the effect of being lowered. In various embodiments, an electric field is applied to draw analyte ions into the mass spectrometer.

  In various aspects, a method is provided for generating analyte ions by laser desorption / ionization of a sample for mass spectrometry. The method includes: an ion source at a first pressure having a surface for supporting a sample deposited thereon; and a laser pulse that strikes at least a portion of the sample on the surface to generate a plume that includes analyte ions. Providing a laser adapted to generate. The method further includes providing a mass spectrometer having an inlet opening to a vacuum chamber at a second pressure lower than the first pressure of the ion source to accept at least a portion of the analyte ions, the ion source The distance between the ion source and the inlet opening is selected to reduce the effects of gas flow velocity effects that are caused by the pressure difference between the ion source and the mass spectrometer and draw molecules from the ion source to the inlet region. In various embodiments, the surface can be a sample plate positioned at an angle of about 0 to about 45 degrees relative to the first ion optical axis of the mass spectrometer, and the laser can be the first ion optical of the mass spectrometer. It can be configured to generate a pulse of energy at an angle of incidence of about 0 to about 80 degrees relative to the axis of the axis. In various embodiments, the surface can be a sample plate capable of tilting a normal at an angle of about 20 to about 45 degrees relative to the first ion optical axis of the mass spectrometer, and the laser can be It can be configured to generate a pulse of energy at an incident angle of about 0 to about 80 degrees relative to the centerline of the first ion optical axis of the meter. In various embodiments, the method includes providing an electric field that is applied to attract analyte ions to the mass spectrometer.

  These and other characteristics of the applicant's teachings will be apparent herein.

  Those skilled in the art will appreciate that the drawings described below are for illustrative purposes only. The drawings are not intended to limit the scope of applicants' teachings, even if:

  In the drawings, like reference numerals indicate like parts.

  The expressions used for the various elements in connection with the applicant's teachings include the meaning of “one or more” or “at least one”, unless expressly stated otherwise. Reference is first made to FIG. 1, which schematically illustrates an ion source 10 for generating ions for mass spectrometry, in accordance with applicants' teachings. Degassing the ion source 10 can be performed to maintain a pressure of about 1 Torr so that the trajectory of ions or neutral particles is not affected by the impact of gas flow during laser ablation. In various embodiments, the ion source pressure can range between about 100 mTorr and about 2 Torr. The ion source 10 having an opening 11 includes a sample plate 14 that can support a sample 16 containing an analyte. In various aspects, the sample 16 can include, but is not limited to, a MALDI matrix. As known in the art, matrix materials include, but are not limited to, a-cyano-4-hydroxy-cinnamic acid (CHCA), 2,5-dihydroxybenzoic acid (DHB). : Dihydroxybenzoic acid), sinamic acid (SA), 3-hydroxypicolinic acid, nicotinic acid-N-oxide, 2,6-dihydroxyacetophenone, and ferulic acid are possible. The normal of the sample plate 14 can be placed at an angle of about 0 to about 45 degrees with respect to the first ion optical axis 18 corresponding to the centerline of the ion path of the mass spectrometer 20, in FIG. The normal of the sample plate is tilted at an angle of about 20 degrees with respect to the first ion optical axis 18. The inlet region 26 of the mass spectrometer 20 includes an inlet cone 28 having an inlet opening 28a and a vacuum chamber 12, which can be lower than the ion source pressure, for example, between about 3 and about 50 mTorr. Can be provided. In various embodiments, the pressure in the vacuum chamber is about 8 mTorr. The laser 22 generates a laser pulse that strikes at least a portion of the sample 16 on the sample plate 14 at an incident angle of about 0 to about 80 degrees with respect to the centerline of the first ion optical axis 18 of the mass spectrometer 20. In various embodiments, the laser can be a high repetition rate laser and can have a pulse rate of about 500 hertz to about 1500 hertz. In various aspects, at least a portion of the sample can be reduced by a laser pulse of a high repetition laser of less than one second. The plume 24 contains analyte ions and neutral contaminants such as matrix material and can be generated according to the trajectory of the incident laser pulse. This directs the plume center away from the entrance region 26 of the mass spectrometer. The weight 28 includes an opening 28a, and in various embodiments, the opening 28a can be 4 mm in diameter. A gas flow is generated by the differential pressure between the ion source 10 and the vacuum chamber 12, which can induce a gas drag force through the inlet region 26 of the mass spectrometer 20. A gas flow under such differential pressure conditions can be the main mode of plume transport. For this reason, as is known in the prior art, analyte ions, neutral particles, and matrix molecules (neutral or charged) are introduced into the gas stream in the vicinity of the inlet region 26 and an opening is formed in the vacuum chamber 12 of the mass spectrometer 20. It can be pulled through 28a. The region affected by the gas flow is referred to as the gas resistance region throughout the application and is indicated by reference numeral 29 in FIG.

  In the present teachings, where there is a differential pressure region, there are two physical forces available to accelerate ions toward the inlet region 26 of the mass spectrometer 20, ie, gas resistance and electric field. The two forces have distinct properties. In particular, the electric field moves only charged particles while gas resistance moves both charged and neutral particles. The combined effect of these two forces can be used to achieve the advantage of achieving high ion transfer efficiency and maintaining a certain degree of distinction between ions and neutral particles.

  According to prior art image processing studies (Puretzky et al., Physical Review Letters, 1999, 83, 444-447), some analyte ions occupy the central axis of the plume while the majority of matrix or other particles Has been pointed out to spread rapidly in the radial direction. The gas resistance just before the opening of the entrance cone to the vacuum chamber is strong and will efficiently draw both ions and neutral particles through the opening. Since the differential pressure across the opening separating these two regions (upstream and downstream of the opening) is sufficiently high, the mean free path between the collisions is such that the loss due to the collision with the wall defining the opening is not very significant. Is much smaller than the orifice diameter of 4 mm in the opening. Subsequent gas expansion injects both analyte ions and neutral contaminants into the vacuum chamber to near depth (eg, a few centimeters) at approximately the speed of sound. Placing the sample plate near the cone opening ensures efficient ion transfer, but allows the inclusion of neutral contaminants in the mass spectrometer along with analyte ions There is. Since the target substance can be placed outside the direct influence of the gas resistance region and can be directed to the ionic gas stream using an electric field, this is an opportunity to distinguish between ions and neutral particles Can provide.

  Optical and analyzer contamination is a particular concern for instruments intended to perform high sample loads. According to the applicant's teachings, it is possible to have an opportunity to distinguish ions from neutral particles. Whether selective transfer of ions to neutral contaminants can be achieved from the differential pressure and focused electric field between the ion source and the vacuum chamber (often referred to as the Q0 optical region), taking advantage of viscous gas resistance. An experiment was planned to investigate. In various embodiments, a significant portion of the neutral components of the rapidly spreading matrix plume can be evacuated in a vacuum system if placed outside the influence of the gas resistance region. The important points in this study are the high transfer efficiency of analyte ions throughout the gas resistance region and the low transfer efficiency in the electric field that focuses while maintaining a certain degree of distinction between ions and neutral particles. To find a reasonable equilibrium point. An experiment was conducted to see that the distinction between ions and neutral particles could be achieved. In order to move the ablation plume in and out of the gas resistance region where the gas resistance force mainly acts, three experiments were conducted with the target substance placed at various distances from the spindle opening. Absolute signal strength was used as a measure of ion transfer efficiency. Measurements of the degree of neutral particle differentiation include laser ablation on a large number of samples and on a lens placed in a vacuum chamber, both visually and measuring loss of signal intensity due to ion optics charging. Tracking of neutral substances was included. Due to the influence of this charge, potential distortion due to build-up of the insulating layer on the ion optical element may occur over time. Laser ablation of a piece of material from one position on the sample plate was defined as “one sample” and the sample was continuously abraded until the absolute signal intensity dropped to less than 50% of the starting condition. The experiment was repeated for two different drug species using a standard CHCA matrix.

  In the first experiment, a laser pulse hitting the sample plate at an angle of incidence of 25 degrees with respect to the center line of the mass spectrometer was used, the inlet opening diameter was 4 mm, and the distance between the sample plate and the inlet opening was 2 mm. It was. At this time, all the plumes were in the gas resistance region, indicating highly efficient ion transfer. On the other hand, this configuration is most susceptible to contamination, clearly showing deposits around the entrance opening and the quadrupole rod in the Q0 region of the vacuum chamber, ablating only 30,000 samples. Although not, the area around the exit opening in the Q0 region was heavily mixed and a 50% signal drop was observed. Evidence for this contamination is shown in FIG. As can be seen from the conditions in which the gas flow is substantially dominant, the potential to direct the ions to the opening was not necessary. In the second experiment, a laser pulse hitting the sample plate at an incident angle of 62 degrees with respect to the center line of the first ion optical axis of the mass spectrometer was used, the entrance aperture diameter was 4 mm, and the sample plate and entrance aperture were The interval between them was 4 mm. It has been found that 70% of the absolute signal strength achieved in experiments with 2 mm spacing is obtained. This configuration, in contrast to the previous configuration, was less susceptible to contamination and on average showed a 50% reduction in the initial signal after ablation of about 40,000 samples. A potential difference of 5 to 30 V was established between the sample plate and the spindle to move the ions toward the cone opening, but did not show any mass dependence and the potential difference was kept constant. I was able to keep it. Part of the ablation plume was outside the gas resistance area where some of the contaminants could be evacuated. This suggests that the laser incident angle can affect the plume trajectory as well, and thus can be a consideration in addition to the distance between the ion source and the inlet opening. In a third experiment, a laser pulse that strikes the sample plate at an incident angle of 80 degrees with respect to the center line of the first ion optical axis of the mass spectrometer and a sample plate that is inclined at an angle of 20 degrees are used. The diameter was 4 mm, and the distance between the sample plate and the inlet opening was 16 mm. The mixing of optical elements was significantly reduced compared to other experiments. A signal drop of 50% was recorded only after more than 200,000 sample ablation. The drift potential between the sample plate and the spindle was 50 to 150 V, which is a higher voltage than the experiment using a 4 mm interval. From this experiment, it can be seen that the function of distinguishing between neutral particles and ions is excellent, and the ions move through the drift region with almost no loss, and from the desorption at the ion source to the cone opening. It was found that even the movement to the club spread. Neutral particles were evacuated before reaching a strong vacuum draw in the gas resistance region near the opening.

Referring to FIG. 2, in various embodiments in accordance with the applicant's teachings, the mass spectrometry system includes an ion source 30 having a sample plate 34 and a mass spectrometer 40 that receives ions generated by the ion source 30. In various embodiments, the ion source pressure can range between about 100 mTorr and about 2 Torr, and can be about 1 Torr. The ion source includes an ion source opening 58. The sample plate 34 can include a sample 36 that includes an analyte. In various aspects, the sample 36 can include, but is not limited to, a MALDI matrix. As is known in the art, matrix materials include, but are not limited to, a-cyano-4-hydroxy-cinnamic acid (CHCA), 2,5-dihydroxybenzoic acid (DHB), cinnamic acid (SA), 3-hydroxy Picolinic acid, nicotinic acid-N-oxide, 2,6-dihydroxyacetophenone, and ferulic acid are possible. The normal of the sample plate 34 can be placed at an angle of about 0 to about 45 degrees with respect to the first ion optical axis 38 corresponding to the centerline of the ion path of the mass spectrometer 40, and in FIG. The normal of the sample plate is tilted at an angle of about 20 degrees with respect to the first ion optical axis 38. The entrance region 46 of the mass spectrometer 40 can include a spindle 54 having an opening 54a. Laser 42 generates a laser pulse that strikes at least a portion of sample 36 on sample plate 34 at an angle of incidence of about 0 to about 80 degrees with respect to the centerline of first ion optical axis 38 of mass spectrometer 40. In various embodiments, the laser 42 can be a high repetition rate laser and can have a pulse rate of about 500 Hertz up to about 1500 Hertz. In various embodiments, at least a portion of the sample 36 can be reduced by a laser pulse of a high repetition laser in less than one second. The plume 24 contains analyte ions and neutral contaminants such as matrix material and can be generated according to the trajectory of the incident laser pulse. In various embodiments, the gas pressure in the vacuum chamber 48 can be between about 3 mTorr and about 50 mTorr. In various embodiments, the gas pressure in the vacuum chamber 48 can be about 8 mTorr. An electric field can be generated to direct the analyte ions of interest along the first ion optical axis 38 into the entrance region 46 of the mass spectrometer 40. The strength of the electric field can be defined by the following formula:
E = V / d (Formula 1)
Here, E represents the strength of the electric field, V represents the first potential applied on the sample plate 34 measured with respect to the potential applied to the spindle 54, and d represents the sample plate 34 of the mass spectrometer 40. And the distance between the opening 54a.

  As described above, the gas resistance and electric field force available to accelerate ions toward the mass spectrometer inlet each have distinct characteristics with respect to particle movement within the analyzer system. That is, gas resistance moves both charged and neutral particles, whereas the electric field moves only charged particles. The gas resistance force can have a greater effect on charged particles than the electric field force on the potential applied in these experiments. Since neutral particles are not charged, they are not affected by the electric field force. In various embodiments of Applicants' teachings, the ablation plume is kept sufficiently away from the inlet region so that the gas drag force does not substantially draw charged and neutral contaminant particles into the mass spectrometer. The geometry of the instrument can be configured, such as the spacing between the ion source and the inlet opening. The plume does not substantially intersect with the gas resistance region, and therefore, when it is placed at a sufficient distance so as not to be substantially affected by the gas resistance generated in the gas resistance region, it exists in the plume when an electric field is applied. Charged analyte ions can be separated from possible neutral contaminant particles. The electric field can direct only charged analyte ions closer to the gas resistance region so that the gas resistance forces can draw analyte ions into the mass spectrometer, thereby reducing system contamination. Using the combined effect of these two forces, it is possible to determine the appropriate instrument geometry to maintain a high degree of ion transfer efficiency while maintaining a certain degree of distinction between ions and neutral particles. . For example, the effect of the electric field force depends on the distance of the sample plate from the entrance region 46 of the mass spectrometer 40 and the potential applied to the sample plate 34 relative to the potential applied to the weight 54. With the applied electric field, ions can be directed to the entrance region 46 of the mass spectrometer 40. In various embodiments, the potential can be from 10V to 250V. In various embodiments, the sample plate 34 can be placed at least 16 mm from the entrance weight 54a of the mass spectrometer 40, the potential on the sample plate 34 is 60V, and 3.75V / mm, ie 3, An electric field strength of 60 V / 16 mm, which is 750 V / m, can be provided.

The effect of gas resistance on the plume is also taken into account in determining the appropriate geometry of the instrument. Although not supported by a particular theory, qualitative guidelines for determining instrument geometry for gas drag force are openings to the hemispheric surface area centered around the inlet opening (eg, It can be estimated from the surface areas of 28a and 54a). At a given distance from the opening (radius “r”), the effect of “drawing” the gas can be approximated by a gas velocity reduction further away from the inlet opening. This reduction can be approximated by the ratio of the area of the inlet opening to the area of the hemisphere at the predetermined distance r. The surface area of the hemisphere can be determined by 2πr ² .

  At a position r away from the inlet opening, the relative gas velocity reduction can be determined as follows:

ここで、Ｄは入口開口部の直径であり、ｒは入口開口部からの距離である。

Here, D is the diameter of the inlet opening, and r is the distance from the inlet opening.

If r is one times the diameter of the opening, the speed decreases through the inlet opening to 1/8 (D / D) ² or 1/8 of the speed. The velocity of the gas flow at this distance is not substantially reduced (as in the case of prior art systems with a 4 mm inlet opening diameter and a 4 mm distance from the sample plate to the inlet opening) and through the inlet opening. Therefore, the amount of contamination entering the mass spectrometer increases with time, and the performance of the mass spectrometer decreases.

If r is 1.5 times the opening diameter, then r = 1.5D and the gas velocity is 1/8 of the velocity through the inlet opening (D / 1.5D) ² or 1 / 8 × 1 / 2.25 = 1/18, which is an improvement over the case where r is equal to one time the opening diameter.

Similarly, further improvements can be achieved if r is twice the opening diameter. In this case, r = 2D and the gas velocity is reduced through the inlet opening to 1/8 (D / 2D) ^{2 of} the velocity, ie 1/8 × 1/4 = 1/32.

Similarly, if r is 3 times the opening diameter, then r = 3D and the gas velocity is further reduced. That is, through the inlet opening, the speed drops to 1/8 (D / 3D) ² or 1/8 × 1/9 = 1/72.

Further improvement can be achieved if r is 4 times the opening diameter, but in this case r = 4D and the gas velocity is 1/8 of the velocity (D / 4D) ² through the inlet opening, ie 1/8 × 1/16 = 1/128. An electric field can be provided to separate charged analyte ions from neutral contaminant particles present in the plume at a distance where the center of the plume does not substantially intersect the gas resistance region. The electric field draws charged analyte ions near the gas resistance region so that the gas drag force pulls analyte ions into the mass spectrometer while neutral particles are not affected by the electric field and enter the mass spectrometer. Can be directed to. This can reduce system contamination.

  As those skilled in the art will appreciate, the analysis will determine how to minimize the effects of neutral particles entering the mass spectrometer from the ablation plume when setting the instrument geometry. Represents a qualitative method. For a more rigorous analysis of the geometry required for the plume to remain substantially outside the gas resistance region, the laser pulse incident angle, ion source gas pressure, and inlet opening diameter are Take other parameters into account.

  In the following equation, ∝ represents a proportional relationship.

The gas velocity V _GAS flowing from the ion source to the inlet opening decreases with the square of the radial distance r from the tip of the inlet opening, as discussed above, and can be determined as follows:

ここで、

here,

は入口開口部へのイオン源ガスの質量流であり、ｒは入口開口部からの距離である。

Is the mass flow of the ion source gas to the inlet opening and r is the distance from the inlet opening.

  Mass flow can be determined from:

ここで、

here,

はオリフィスに入るイオン源気体の質量流であり、Ｍはイオン源気体の分子量であり、Ｔ_０はイオン源気体の温度であり、ｐ_０はイオン源気体の圧力であり、Ｄは入口開口部の直径である。

Is the mass flow of the ion source gas entering the orifice, M is the molecular weight of the ion source gas, T ₀ is the temperature of the ion source gas, p ₀ is the pressure of the ion source gas, and D is the inlet opening. Is the diameter.

  Replacing Equation 4 with Equation 3 gives:

レーザアブレーションプルーム内に含まれる中性混入物質は、ある速度Ｖ_{ＰＬＵＭＥ}で、気体流優勢領域の、所定半径距離ｒ＝Ｒ（図９参照）外で動き、気体流の速度Ｖ_ＧＡＳが非常に遅いため、中性粒子は気体流場に引き込まれることもなく、引っぱられて入口開口部を通ることもない。よって、システムの混入が減少する。Ｖ_{ＰＬＵＭＥ}とＶ_ＧＡＳとの間の関係は以下のように記述できる：
ＡＶ_{ＰＬＵＭＥ}＞Ｖ_ＧＡＳ （式６）
ここで、Ａは１の近似値と比例する定数である。

Neutral contaminants contained in the laser ablation plume move outside a predetermined radial distance r = R (see FIG. 9) in the gas flow dominant region at a certain velocity V _PLUME and the gas flow velocity V _GAS is very slow. Thus, the neutral particles are not drawn into the gas flow field and are not drawn through the inlet opening. Thus, system contamination is reduced. The relationship between V _PLUME and V _GAS can be described as follows:
AV _PLUME > V _GAS (Formula 6)
Here, A is a constant proportional to the approximate value of 1.

  Replacing Equation 5 with Equation 6 gives:

これは式２に類似しており、ｐ_０、Ｔ_０およびＭは定数である。

This is similar to Equation 2, where p ₀ , T ₀ and M are constants.

When constants A, M, T ₀ , and V _PLUME are _combined into constant B and Equation 7 is transformed by solving for distance r = R, the following mathematical relational expression for obtaining the radius of the gas flow dominant region is obtained. Is:

図９に示すように、プルームが実質的に気体抵抗領域の外に留まるのに必要な幾何学的形状を、以下の式から求めることができる：

As shown in FIG. 9, the geometric shape required for the plume to remain substantially outside the gas resistance region can be determined from the following equation:

ここで、θは機器のイオン経路の中心線とプルームとの間の角度であり、Ｒは気体流優勢領域の所定半径であり、Ｌはサンプルプレートと入口開口部との間の距離である。

Where θ is the angle between the centerline of the ion path of the instrument and the plume, R is the predetermined radius of the gas flow dominant region, and L is the distance between the sample plate and the inlet opening.

  Replacing Equation 8 with Equation 9 gives:

ここで、定数Ｂは中性粒子によるシステムの混入の測度であり、Ｂが大きいことはサンプル毎の混入が少ないことを示す。

Here, the constant B is a measure of the mixing of the system with neutral particles, and a large B indicates that there is little mixing for each sample.

For example, in a commercially available QSTAR® system (Applied Biosystems / MDS Sciex), p ₀ = 1 torr, D = 4 mm, L = 4 mm, and θ = 62 degrees. To construct a system that can reduce contamination better than a QSTAR system, B is chosen to be 1 torr ^-1/2 or 1, which gives the following equation:

ここで、ｐ_０がトルで表されれば、同式は無単位とみなすことができる。

Here, if p ₀ is expressed in torr, the equation can be regarded as unitless.

Therefore, by increasing the angle θ, or increasing the distance L between the sample plate and the inlet opening, or decreasing the diameter D of the inlet opening, or decreasing the ion source pressure p ₀ , Mixing can be reduced compared to the prior art.

  Lowering the ion source pressure is not an efficient or practical design consideration because the relationship given by Equation 10 is non-linear (square root). For example, to achieve the same effect of increasing the distance between the sample plate and the inlet opening from 4 mm to 16 mm, the ion source pressure is reduced by a factor of 16 (in various embodiments, to 60 mtorr). This needs to be done, but this is far from the normal work area. Changing the diameter of the inlet opening has other detrimental effects on the design of the device. For example, increasing the diameter increases the pumping load to maintain the vacuum pressure at the desired level, necessitating the use of a large, expensive pump. On the other hand, when the diameter is reduced, the ion transfer efficiency is affected, which in turn affects the sensitivity. Therefore, in practical considerations, it tends to be preferred to make adjustments for either the angle θ or the distance between the sample plate and the inlet opening.

For example, if the inlet opening diameter D is 4 mm, p ₀ is 1 Torr, B is 1 Torr ^−1/2 , and the angle θ, which is the angle between the centerline of the instrument ion path and the plume, is 0 to 80 degrees are possible, and the distance L between the sample plate and the inlet opening is calculated as shown in Table 1 and Table 1 (Note: Inlet opening can reduce the contamination entering the system. The following values were calculated for an example where the part diameter D was 4 mm, p ₀ was 1 torr, and B was 1 torr ^-1/2 .)

マトリクスが用いられる場合、プルーム４４中には中性粒子もマトリクス分子も存在し得る。プルーム４４が入射レーザビーム４２に向けた方向で移動する傾向があることは公知である（Ｒａｐｉｄ Ｃｏｍｍｕｎｉｃａｔｉｏｎｓ ｉｎ Ｍａｓｓ Ｓｐｅｃｔｒｏｍｅｔｒｙ、１９９５、９、５１５−５１８；Ｉｎｔｅｒｎａｔｉｏｎａｌ Ｊｏｕｒｎａｌ ｏｆ Ｍａｓｓ Ｓｐｅｃｔｒｏｍｅｔｒｙ、１９９８、１７７、１１１−１１８；Ｒａｐｉｄ Ｃｏｍｍｕｎｉｃａｔｉｏｎｓ ｉｎ Ｍａｓｓ Ｓｐｅｃｔｒｏｍｅｔｒｙ、１９９９、１３、７９２−７９７）。上で示すとおり、出願人の教示の種々の実施形態の幾何学的形状により、プルーム４４と気体抵抗領域５６とを十分に離すことができるため、質量分析計に入る混入物質を実質的に減らすことができる。この方式で、プルーム４４中に存在し得て、システムの混入になりやすい中性粒子およびマトリクス分子は、実質的に電場の影響を受けず、質量分析計４０の第１イオン光学軸３８の中心線に対して約０から約８０度の入射角にあるレーザビーム４２に向かい、且つ質量分析計４０の入口領域４６から離れる軌道に従う。

If a matrix is used, neutral particles and matrix molecules may be present in the plume 44. It is known that plume 44 tends to move in the direction towards incident laser beam 42 (Rapid Communications in Mass Spectrometry, 1995, 9, 515-518; International Journal of Mass Spectrometry, 1998, 177, 111-118). Rapid Communications in Mass Spectrometry, 1999, 13, 792-797). As indicated above, the geometry of the various embodiments taught by the applicant allows the plume 44 and the gas resistance region 56 to be sufficiently separated, thereby substantially reducing contaminants entering the mass spectrometer. be able to. In this manner, neutral particles and matrix molecules that may be present in the plume 44 and are prone to system contamination are substantially unaffected by the electric field and are centered on the first ion optic axis 38 of the mass spectrometer 40. Follow a trajectory that is directed to the laser beam 42 at an incident angle of about 0 to about 80 degrees to the line and away from the entrance region 46 of the mass spectrometer 40.

  As shown in FIG. 2, the electrode 50 can be placed between the sample plate 34 and the entrance region 46 of the mass spectrometer 40, and a second potential is applied to the electrode 50 relative to the potential applied to the weight 54. The analyte ions can be directed away from the laser beam 42 and directed along the second ion optical axis 52 into the entrance region 46 of the mass spectrometer 40. The electrode can be a conductive element to which a potential is applied and can be, but is not limited to, a plate, annulus, rod or tube. The electrode 50 directs analyte ions into the entrance region 46 of the mass spectrometer 40, so that various methods can be used between the sample plate 34 and the entrance region 46 of the mass spectrometer 40 as is known in the art. Can be set in position. In various embodiments, the second potential between the potential of the spindle 54 and the potential of the plate 34 can drift. In various embodiments, the second potential can be from 20 to 250V, and in various aspects, the electrode 50 can be the same potential as the sample plate 34. The second potential can be applied in association with the potential between the sample plate or independently from the first potential. Even if the second potential between the electrode 50 and the spindle 54 cannot direct analyte ions to the entrance region 46 of the mass spectrometer 40, a potential is similarly applied between the sample plate and the spindle. It can be applied independently.

  Referring to FIG. 3, in various embodiments in accordance with Applicant's teachings, a mass spectrometry system is generated by an ion source 60 having a sample plate 64 that can include a sample 66 containing an analyte, and the ion source 60. And a mass spectrometer 70 for receiving ions. The ion source includes an opening 62, and in various embodiments, the ion source pressure can range from about 100 mTorr to about 2 Torr, and can be about 1 Torr. In various embodiments, the sample plate 64 is substantially substantially relative to the first ion optic axis 68 of the mass spectrometer 70 such that the sample plate 64 is at a 0 degree tilt angle with respect to the first ion optic axis. Orthogonal to The mass spectrometer 70 can include a spindle 84 having an opening 84 a and a vacuum chamber 78. A gas flow is generated by the differential pressure between the ion source 60 and the vacuum chamber 78, which can induce a gas drag force through the inlet region 76 of the mass spectrometer 70. Laser 72 generates a laser pulse that strikes at least a portion of sample 66 on sample plate 64. A laser ablation plume 74 can be generated that includes analyte ions. Thereby, in the vicinity of the inlet region 76, the gas resistance region 86 takes in analyte ions, neutral particles, and matrix molecules (either neutral or charged) and opens them in the vacuum chamber 78 of the mass spectrometer 70. It can be pulled in through 84a. In various embodiments of the applicant's teachings, the laser ablation plume is kept sufficiently away from the gas resistance region so that the gas resistance does not substantially pull charged and neutral contaminant particles into the mass spectrometer. As such, the instrument geometry can be configured, such as the spacing between the ion source and the inlet opening. If the electric field is applied at a sufficient distance so that the plume does not substantially intersect the gas resistance region and therefore the plume is not substantially affected by the gas resistance generated in the gas resistance region, Analyte ions are directed along the first ion optic axis 68 to the entrance region 76 of the mass spectrometer 70, thereby separating charged analyte ions from neutral contaminant particles that may be present in the plume. In contrast, neutral contaminant particles will not be affected by the electric field.

  FIG. 4 shows a photograph of severe contamination 80 that can accumulate on a lens (such as lens 82 shown in FIG. 3) in a prior art mass spectrometer after approximately 30,000 samples have been analyzed in a prior art system. Show. Because lenses typically have only 1.5 mm openings, small contaminants on the lens can significantly reduce the flow rate of ions through the mass spectrometer. The contamination seen in 4 is considered serious. The black circle in the middle of the photograph is the lens opening and the contaminants that entered the system accumulated around the opening (indicated by reference numeral 80). Note that the four black rings arranged in contrast around the lens opening indicate the end of the quadrupole rod in the Q0 region of the mass spectrometer.

  FIG. 7 illustrates that analyte ions 188, neutral particles and matrix molecules 187 in the vicinity of the entrance region 176 of the mass spectrometer 170 can be captured and can be drawn into the mass spectrometer 170 through the cone 184. The mass spectrometer inlet region 186 is shown. FIG. 8 illustrates how the gas resistance region 156 can be separated from the plume 144 according to various embodiments of the applicant's teachings. Further, the parameters given by equations 1 and 2 are shown in FIG. Analyte ions 145 can be drawn into the mass spectrometer 140 and neutral particles 143 can follow the plume 144 in the direction of the laser beam 142.

  FIG. 5 shows an example of comparing the sensitivity of a prior art ion source with the applicant's ion source for the number of samples treated with the compound haloperidol. The relative signal indicates a signal normalized to the signal obtained from a clean system with a sample number equal to 1. As can be seen in FIG. 5, as the number of samples analyzed increases, the sensitivity decreases with prior art systems, and when the number of analyzed samples exceeds about 30,000, the sensitivity decreases significantly. In a system constructed according to Applicants' teachings, the sensitivity was almost constant even after 180,000 samples were analyzed.

  In a further example, the sample was analyzed under the same settings as for a system constructed according to applicant's teachings. The following parameters were used: The pressure in the vacuum chamber is 8 mTorr, the laser repetition rate is 1 kHz, the pulse energy is 2.5-3.5 μJ, the voltage on the spindle is 0 volts, and the voltage on the sample plate is 60V. The compound analyzed was prazosin. FIG. 6 shows the sensitivity of prazosin analysis to a second potential applied to an electrode, such as electrode 50 shown in FIG. 2, when the first potential applied to the sample plate is 60V. Sensitivity is normalized to the sensitivity obtained when the electrode potential is grounded. The sensitivity increases in this case until it is approximately the same as the potential on the electrode of 60V resulting in an electric field strength of 60V / 16mm where the potential on the sample plate is 3.75V / mm or 3,750V / m.

  The following describes the general use of applicant's teachings, which is not limited to any particular embodiment, but is applicable to any embodiment. In operation, a high repetition rate solid-state laser is possible, but not limited, to a portion of the sample containing the analyte on a tilted sample plate. A plume containing the analyte ions can be generated and moves away from the entrance region of the mass spectrometer towards the incident laser beam. Analyte ions are typically generated at pressures from about 0.2 Torr to about 2 Torr for high pressure MALDI applications, as is known in the art. Neutral and matrix particles that may be present in the plume can enter the mass spectrometer entrance region and can contaminate the system when deposited near the ion trajectory, generally near the ion trajectory. In the applicant's teachings, both ions, and neutral and matrix particles, if any, follow an initial trajectory away from the entrance region of the mass spectrometer towards the incident laser beam. This allows neutral particles and contaminants to be deposited where they do not affect the ion trajectory, which dramatically improves the signal quality of the system after processing a large number of samples. Can do. On the other hand, the sensitivity of the system is low because the initial trajectory of ions is similarly distant from the entrance region of the mass spectrometer. Thus, if an electric field applying a first potential is generated, analyte ions can be directed to the entrance region of the mass spectrometer. The second potential is applied either independently or in conjunction with the first potential, and the analyte is near a gas resistance region that allows analyte ions to be drawn into the inlet opening of the mass spectrometer by gas resistance. Ions can be directed.

  While the applicant's teachings are described in connection with various embodiments, it is not intended that the applicant's teachings be limited to such embodiments. On the contrary, as will be appreciated by those skilled in the art, Applicants' teachings encompass various alternatives, modifications, and equivalents.

  In various embodiments, the distance between the sample plate and the inlet opening can be 5 millimeters or more. In various embodiments, the distance between the sample plate and the inlet opening can be 6 millimeters or more. In various embodiments, the distance between the sample plate and the inlet opening can be 10 millimeters or more. In various embodiments, the distance between the sample plate and the inlet opening can be between 5 and 20 millimeters. In various embodiments, the distance between the sample plate and the inlet opening can be between 12 and 20 millimeters. In various embodiments, the distance between the sample plate and the inlet opening can be 16 millimeters.

  In various embodiments, the use of a high repetition laser allows data to be acquired quickly and a speed of about 1 second or less can be achieved for each sample point on the sample plate. A high repetition laser can be used to obtain thousands of laser shots per sample in a few seconds, thereby improving overall accuracy and obtaining high throughput screening of samples. Typically, in such a high-throughput system, the sample can be analyzed quickly, but contaminant accumulation can occur in a short time. For example, after analyzing about 30,000 samples in a prior art system, the performance can be noticeably degraded as the system needs to be cleaned. The vacuum needs to be broken when the system needs to be cleaned, which can be a significant downtime for the system. Applicant's teachings can reduce the frequency of system cleaning and thus reduce downtime, which is particularly important for high throughput applications.

  In various embodiments, the sample can include a MALDI matrix, but especially for samples where the mass range is limited by matrix interference, samples without a matrix can be used as well. An example of a matrix-free technique is desorption / ionization on silicon (DIOS), where analyte ions are trapped in a porous silicon surface that is laser desorbed and ionized. (Nature, 1999, 399, 243-246). The absence of matrix interference allows the analysis of small molecules below 300 m / z. Samples without a matrix can be used, but neutral particles and other contaminants can be present, thus forming a deposit that can be introduced into the system.

  Although the sample plate shown in the figure represents a typical plate, Applicants' teaching is not limited to such a configuration. Other configurations of sample plates known in the art can be used. For example, the sample plate can include topological features as is known in the art. The sample plate can be a bent disk shape or can include other materials such as tape.

  In various embodiments, the electrode can be a conductive element that is energized. The electrodes can be, but are not limited to, plates, rings, rods or tubes.

In various embodiments, the mass spectrometer can be, but is not limited to, a mass spectrometer capable of utilizing single MS, tandem (MS / MS), or multidimensional (MS ⁿ ) mass spectrometry. Mass spectrometers include, but are not limited to, triple quadrupole, ion trap, hybrid linear ion trap, time of flight, quadrupole time of flight, RF multipole, magnetic sector, electrostatic sector, and ion mobility spectrometer Is possible. The mass spectrometer can be, but is not limited to, a mass filter, mass selector, ion focusing and / or ion steering element, such as an ion guide. The mass spectrometer can be, but is not limited to, ion reflectors and / or ion fragmentors, such as collision cells, photolysis cells, and surface resolution fragmentors.

  All references and similar documents cited in this application, including but not limited to patents, patent applications, articles, books, papers, and web pages and similar materials All materials are expressly incorporated by reference. One or more of the incorporated literature and similar materials, including, but not limited to, defined terms, use of phrases, described techniques, or otherwise, are different or inconsistent with this application In such cases, the present application takes precedence.

  Although the applicant's teachings have been particularly shown and described with reference to specific exemplary embodiments, various changes in form and detail may be made without departing from the spirit and scope of the teachings. Should be understood. Accordingly, all embodiments and equivalents that fall within the scope and spirit of the teachings are claimed. Applicant's teaching method descriptions and drawings should not be read as limited to the described order of elements unless stated to that effect.

  While the applicant's teachings have been described in connection with various embodiments and examples, it is not intended that the applicant's teachings be limited to such embodiments and examples. On the contrary, as those skilled in the art will appreciate, applicant's teachings include various alternatives, modifications, and equivalents, all of which are within the scope and scope of the present invention. It is considered a thing.

1 schematically illustrates an ion source according to various embodiments of applicants' teachings. 1 schematically illustrates a mass spectrometer system with a tilted sample plate according to various embodiments of the applicant's teachings. 1 schematically illustrates a mass spectrometer system according to various embodiments of the applicant's teachings. After approximately 30,000 samples have been analyzed, a typical contamination pattern on a lens placed in the vacuum region of a prior art mass spectrometer with a MALDI source is shown. The sensitivity of the prior art ion source and the applicant's ion source is compared against the amount of sample material analyzed. According to the applicant's teachings, when the potential on the sample plate relative to the inlet cone is 60 V, the instrument sensitivity measurement results for the potential between the mass spectrometer electrode and the inlet cone are shown. 1 schematically illustrates a prior art mass spectrometer system showing the effect of a gas resistance region on ions and neutral molecules in a plume. 1 schematically illustrates a mass spectrometer system according to various embodiments of the applicant's teachings showing separation of a gas resistance region from a plume. 1 schematically illustrates a mass spectrometer system according to various embodiments of the applicant's teachings that exhibits parameters that can be varied to minimize contamination.

Claims (51)

An ion source that generates ions by laser desorption / ionization for analysis by a mass spectrometer, the mass spectrometer comprising an inlet region opening and the first pressure of the ion source A vacuum chamber at a lower second pressure, the ion source comprising:
The sample plate for supporting a sample deposited on the sample plate;
An incident angle is about 0 to 80 degrees with respect to the centerline of the first ion optical axis of the mass spectrometer and is configured to generate a laser pulse that hits at least a portion of the sample on the sample plate; A laser adapted to generate a plume comprising analyte ions and neutral molecules;
The angle of incidence of the laser pulse configured to reduce neutral molecules drawn into the inlet region opening by a gas flow resulting from a pressure difference between the ion source region and the mass spectrometer; and the sample A combination of the distance between the plate and the inlet region opening;
An ion source.   The ion source of claim 1, wherein the laser pulse strikes the sample plate at an angle greater than about 20 degrees with respect to the first ion optical axis of the mass spectrometer.   The ion source of claim 1, wherein the sample plate normal is at a position of about 0 to about 45 degrees with respect to the first ion optical axis of the mass spectrometer.   The ion source of claim 1, wherein the normal of the sample plate is tilted at an angle of about 20 to about 45 degrees with respect to the first ion optical axis of the mass spectrometer.   5. The ion source according to any one of claims 1, 2, 3, or 4, wherein the sample plate is at a position about 5 mm or more from the entrance region opening of the mass spectrometer.   5. The ion source according to any one of claims 1, 2, 3, or 4, wherein the sample plate is about 16 mm from the entrance region opening of the mass spectrometer.   5. The ion source according to any one of claims 1, 2, 3, or 4, wherein the sample plate is at a position between 5 and 20 mm from the entrance region opening of the mass spectrometer.   5. The ion source according to any one of claims 1, 2, 3, or 4, wherein the sample plate is at a position between 12 and 20 mm from the entrance region opening of the mass spectrometer.   The ion source of claim 1, wherein when the plume is separated from the sample plate, the center of the plume is directed substantially away from the entrance region.   The ion source of claim 1, wherein an electric field is applied to draw analyte ions into the inlet region of the mass spectrometer.   The ion source of claim 1, wherein the gas pressure of the vacuum chamber of the mass spectrometer is from about 3 mTorr to about 50 mTorr.   The ion source of claim 1, wherein the gas pressure of the vacuum chamber of the mass spectrometer is about 8 mTorr.   The ion source of claim 1, wherein the laser is a high repetition rate laser.   The ion source according to claim 13, wherein a pulse rate of the laser is between 200 Hz and 5000 Hz.   The ion source of claim 1, wherein the sample comprises a MALDI matrix.   The mass spectrometer comprises at least one of a triple quadrupole, ion trap, hybrid linear ion trap, quadrupole time of flight, RF multipole, magnetic sector, electrostatic sector, ion mobility spectrometer, and ion reflector. The ion source according to claim 1, comprising: A system for generating analyte ions by laser desorption / ionization of a sample for analysis by a mass spectrometer, the mass spectrometer having an inlet region opening for receiving analyte ions in a vacuum chamber The system has
A sample plate for supporting a sample deposited on the sample plate, being at a first pressure and being an ion source for generating analyte ions, wherein the analyte ions are An ion source received in a vacuum chamber at a second pressure lower than one pressure;
An incident angle is from about 0 to about 80 degrees with respect to the centerline of the first ion optical axis of the mass spectrometer and is configured to generate a laser pulse that strikes at least a portion of the sample on the sample plate. A laser adapted to produce a plume comprising analyte ions and neutral molecules;
The angle of incidence of the laser pulse configured to reduce neutral molecules drawn into the inlet region opening by a gas flow resulting from a pressure difference between the ion source region and the mass spectrometer; and the sample A combination of the distance between the plate and the inlet region opening;
A system comprising:   The system of claim 17, wherein the laser pulse strikes the sample plate at an angle greater than about 20 degrees with respect to the first ion optical axis of the mass spectrometer.   The system of claim 17, wherein the normal of the sample plate is at a position of about 0 to about 45 degrees with respect to the first ion optical axis of the mass spectrometer.   The system of claim 17, wherein the normal of the sample plate is tilted at an angle of about 20 to about 45 degrees with respect to the first ion optical axis of the mass spectrometer.   21. The system of any one of claims 17, 18, 19, or 20, wherein the sample plate is about 5 mm or more from the entrance region of the mass spectrometer.   21. A system according to any one of claims 17, 18, 19, or 20, wherein the sample plate is approximately 16 mm from the entrance region opening of the mass spectrometer.   21. The system of any one of claims 17, 18, 19, or 20, wherein the sample plate is between 5 and 20 mm from the entrance region opening of the mass spectrometer.   21. The system of any one of claims 17, 18, 19, or 20, wherein the sample plate is at a position between 12 and 20 mm from the entrance region opening of the mass spectrometer.   18. The system of claim 17, wherein when the plume leaves the sample plate, the plume center is oriented substantially away from the inlet region.   The system of claim 17, wherein an electric field is applied to draw analyte ions into the entrance region of the mass spectrometer.   The system of claim 17, wherein the gas pressure in the vacuum chamber of the mass spectrometer is from about 3 mTorr to about 50 mTorr.   The system of claim 17, wherein the gas pressure in the vacuum chamber of the mass spectrometer is about 8 mTorr.   The system of claim 17, wherein the laser is a high repetition rate laser.   30. The system of claim 29, wherein the laser pulse rate is between 200 Hz and 5000 Hz.   The system of claim 17, wherein the sample comprises a MALDI matrix.   The mass spectrometer comprises at least one of a triple quadrupole, ion trap, hybrid linear ion trap, quadrupole time of flight, RF multipole, magnetic sector, electrostatic sector, ion mobility spectrometer, and ion reflector. The system of claim 17, comprising: A method for generating analyte ions by laser desorption / ionization of a sample for analysis by a mass spectrometer, the mass spectrometer having an inlet region opening and a vacuum chamber, the method comprising:
Providing at a first pressure an ion source having the sample plate for supporting a sample deposited on the sample plate at a first pressure and adapted to generate a laser pulse that strikes at least a portion of the sample on the sample plate Providing a laser that produces a plume comprising analyte ions and neutral molecules;
Providing a mass spectrometer having an entrance region opening to a vacuum chamber at a second pressure lower than the first pressure of the ion source to accept at least a portion of the analyte ions; A combination of the angle of incidence of the pulse and the distance between the sample plate and the inlet region opening is the gas flow generated by the pressure difference between the ion source region and the mass spectrometer at the inlet region opening. A process configured to reduce neutral molecules drawn; and
Including methods.   The laser generates a laser pulse having an incident angle of about 0 to about 80 degrees relative to a centerline of the first ion optic axis of the mass spectrometer and hitting at least a portion of the sample on the sample plate. 34. The method of claim 33, configured as follows.   34. The method of claim 33, wherein the laser pulse strikes the sample plate at an angle greater than about 20 degrees with respect to the first optical axis of the mass spectrometer.   34. The method of claim 33, wherein the normal of the sample plate is at a position of about 0 to about 45 degrees with respect to the first ion optical axis of the mass spectrometer.   34. The method of claim 33, wherein the normal of the sample plate is tilted at an angle of about 20 to about 45 degrees with respect to the first ion optical axis of the mass spectrometer.   38. The method of any one of claims 33, 34, 35, 36, or 37, wherein the sample plate is about 5 mm or more from the entrance region opening of the mass spectrometer.   38. The method of any one of claims 33, 34, 35, 36, or 37, wherein the sample plate is approximately 16 mm from the entrance region opening of the mass spectrometer.   38. The method of any one of claims 33, 34, 35, 36, or 37, wherein the sample plate is between 5 and 20 mm from the entrance region opening of the mass spectrometer.   38. A method according to any one of claims 33, 34, 35, 36, or 37, wherein the sample plate is at a position between 12 and 20 mm from the entrance region opening of the mass spectrometer.   34. The method of claim 33, wherein when the plume leaves the sample plate, the plume center is oriented substantially away from the inlet region.   34. The method of claim 33, wherein an electric field is applied to draw analyte ions into the entrance region of the mass spectrometer.   34. The method of claim 33, wherein the gas pressure in the vacuum chamber of the mass spectrometer is from about 3 mTorr to about 50 mTorr.   34. The method of claim 33, wherein the gas pressure in the vacuum chamber of the mass spectrometer is about 8 mTorr.   34. The method of claim 33, wherein the laser is a high repetition rate laser.   47. The method of claim 46, wherein the laser pulse rate is between 200 Hz and 5000 Hz.   34. The method of claim 33, wherein the sample comprises a MALDI matrix.   The mass spectrometer comprises at least one of a triple quadrupole, ion trap, hybrid linear ion trap, quadrupole time of flight, RF multipole, magnetic sector, electrostatic sector, ion mobility spectrometer, and ion reflector. 34. The method of claim 33, comprising. A mass spectrometer system for generating and analyzing ions from a sample;
An ion source having a sample plate for supporting a sample deposited on the sample plate at a first pressure, and a second pressure lower than the first pressure of the ion source, the inlet opening having a predetermined diameter A mass spectrometer, wherein the sample plate and the inlet opening are separated by a predetermined distance;
An analyte ion and a neutral molecule configured to generate a laser pulse that strikes at least a portion of the sample on the sample plate at a predetermined angle of incidence with respect to a centerline of the first ion optical axis of the mass spectrometer A laser adapted to produce a plume comprising:
With
The mass spectrometer system has the following formula:

To reduce neutral molecules drawn into the inlet opening, where θ is the predetermined angle of incidence, p ₀ is the pressure of the ion source in torr, and D is the inlet The system, wherein the predetermined diameter of the opening and L is the predetermined distance between the sample plate and the inlet opening.   The predetermined distance between the sample plate and the inlet opening is 16 mm, and the predetermined incident angle with respect to the center line of the first ion optical axis of the mass spectrometer is about 0 to about 80 degrees; 51. The system according to claim 50.

Images