RU2640393C2 - Method for analyzing impurities in liquids or gases during their microchannel outflow in vacuum under supersonic gas flow influence containing ions and metastable excited atoms with formation and transportation of analyzed ions in rf linear trap linked to mass analyzer - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: method provides extraction of ions or their formation from a solution or gas that enters the radiofrequency linear trap of the gas dynamic interface through a microscopic size capillary. The evaporation of the liquid is maintained by the influx of heat from the supersonic gas jet leaving the heated channel. The jet is directed to the outlet end of the capillary, which is surrounded by a cylindrical shell with an inlet for injecting a jet, which stimulates the outlet or formation of the analyzed ions. It is possible to preliminary separate the analyzed ions from the solution by their isoelectric points before entering the capillary and by mobilities during movement inside the capillary under the action of an electric field. Also, ions from the gas mixture and from the solution can be isolated due to differences in the adsorptivity of the corresponding compounds on the chamber walls and with differences in the yield rates of these compounds from the capillary. The trap is coupled to a mass analyzer, for example, a time-of-flight mass spectrometer with orthogonal ion injection.

EFFECT: possibility of characterizing biomolecules in solutions by the equilibrium probabilities of holding different charge carriers by their separate functional groups.

21 cl, 9 dwg

Description

FIELD OF THE INVENTION

The present invention relates to methods and techniques for chemical analysis of impurity compounds and ions in gas mixtures and in liquid solutions, including multiply charged ions of biomolecules, when they are extracted from a liquid or the formation of analyzed ions under the influence of a gas stream containing ions and metastable excited atoms. These methods may include a combination of the separation of the analyzed ions by adsorption capacity on the walls of the inlet chamber, and for biomolecule ions by the isoelectric point before the solution is introduced into the micron-diameter channel and by mobility when moving inside the channel. Registration and analysis of molecular ions and their product ions in terms of mass-to-charge ratios can be performed using a time-of-flight mass spectrometer with orthogonal ion input (ortho-VPMS) or on some other mass analyzer. The characterization of the spatial structure of ions of biomolecules can be achieved on the basis of decomposition of the multidimensional charge distributions of their recorded ions, due to the retention of various sets of charge carriers present in the solution.

Among the tasks for which, in addition to sensitivity, both the separation ability and the dynamic measurement range are important, rapid analysis of microimpurities in gases, in water and other liquids as applied to safety, customs and environmental control systems can be mentioned. Real-time analysis of gas and liquid mixtures of various origins can also be important for a variety of technological, medical and other applications.

BACKGROUND

After the development and creation at our institute of the first time-of-flight mass spectrometers with orthogonal ion injection (ortho-VPMS) [1,2], devices of this type became widespread in solving various analytical and structural problems [3-5]. The convenience of connecting such devices, in particular, with an ion source based on the electrospray of liquids, made them effective for studying the composition and structure of ions of various nature that were originally present in the solution. At the same time, there are important problems, including in the analysis of liquid samples, for which the applicability, sensitivity, separation ability and "information performance" of known instrument systems, including ortho-VPMS, are insufficient. To overcome these limitations, it is natural to strive to introduce alternative methods for producing ions into the mass spectrometric experiment and transport them to the vacuum part of the device, and to use additional measurement dimensions associated with controlled transformations of the studied ions and data recording during these transformations.

A possible method of extracting ions from a liquid, at least from the point of view of the expected sensitivity of the analysis, is field evaporation of ions. Despite the fact that the phenomenon of field evaporation of ions has been studied for a long time [6,7], the details and conditions of the transition of ions from the liquid phase to the gas phase are still poorly understood. In particular, this relates to the question of the influence of the ion charge on the efficiency of their exit from the liquid in electric fields. The bulk of the work on field evaporation of ions is associated with the study of the mechanism of ion formation during the electrospray of polar solutions [8, 9]. However, existing experimental methods using the electrospray of solutions do not allow obtaining information on primary ions leaving charged microdrops.

The electrospray of solutions is most widely used in mass spectrometry of heavy organic ions [10]. It is believed that field evaporation of ions is one of the main mechanisms responsible for the yield of relatively small ions during electrospray. At the same time, the mechanism of extraction of large multiply charged ions from a liquid is still the subject of discussion [11-14]. It can be expected that for multiply charged ions having a complex structure, the question of the efficiency of field evaporation from solutions does not have such an unambiguous answer.

One more important feature of the field evaporation of ions from liquids should be taken into account, namely, that the phase boundary is crossed not by an isolated ion, but by an ion cluster, which includes several polar liquid molecules [8, 9, 15]. This circumstance usually complicates the solution of analytical problems. Therefore, it is desirable to decluster the studied ions before entering them into the mass analyzer.

The possibility of creating conditions for direct field evaporation of ions from polar solutions without spraying was first demonstrated in [16, 17]. The stabilization of the liquid surface in a strong electric field was ensured due to the fact that the solution containing ions was placed in the channels of the polymer track membrane, the diameter of which was several tens of nanometers. Subsequently, it was shown that under stationary conditions, a strong local electric field capable of stimulating the effective exit of ions from the polar liquid is created due to the charging of the surface of the dielectric membrane. This technique of extraction of ions from solutions has a number of significant drawbacks that limit its use, in particular, in analytical applications.

One way to overcome these difficulties is described in the RF patent for the invention [18]. The main idea of this approach is to use electric field pulses with a duration sufficient for extraction of relatively light ions from the liquid, but incapable of leading to a significant movement and leakage of liquid from the membrane channels.

The impact on the membrane surface of a supersonic gas flow, especially when it contains metastable excited atoms, as described in our patent application [19], can also overcome the difficulties described. In addition, ions can be formed from neutral molecules of the solution, and initially ionized compounds in the solution are transformed by the action of metastable excited atoms, which can expand the analytical capabilities of this approach. The analysis method described in this application is a prototype of the present invention. Its main disadvantages are associated precisely with the use of a track membrane, the nanoscale channels of which in real conditions are not capable of long-term operation. This leads to the need for a fairly frequent replacement of the membrane in the described source. In addition, placing the membrane at some distance from the radio frequency quadrupole should lead to noticeable losses of the analyzed ions. The use of capillaries with a micron-sized channel characteristic of nanospray ion sources, as proposed in the present invention, and their introduction into the radio-frequency quadrupole will significantly remove these problems.

In the past 20 years, gas-filled radio frequency multipoles, devices containing a set of rods parallel to each other, symmetrically located around the axis of the device, have become widespread in mass spectrometry. The phase-shifted RF voltages are applied to adjacent rods. These devices are usually used as a means of focusing and efficiently transporting ions or for accumulating ions (in this case they are called linear radio frequency traps or linear ion traps) with the possible isolation of selected ions and conducting controlled dissociation and other structural transformations [20-22]. In these devices, the property of high-frequency force fields described in Mechanics of Landau and Lifshitz [23] is used to cause the particles to be pushed out in such fields to reduce the strength of these fields. More precisely, the average particle motion in such fields is described, to a first approximation, by the effective potential, which is directly proportional to the square of the high-frequency electric field multiplied by the square of the particle’s charge and inversely proportional to the particle’s mass. For a special case of an ideal radio-frequency quadrupole, the effective potential depends quadratically on both coordinates (in a rectangular coordinate system in a plane orthogonal to the axis of the quadrupole), reaching a minimum value on the axis of the quadrupole. The averaged free movement of ions in such a field (in the absence of other external fields, collisions with residual gas molecules, and neglecting ion-ion interactions) are independent harmonic oscillations in both coordinates. In these devices, used as ion storage rings and reactors, two important properties in this case - the ability to accumulate ions and the ability to separate these ions can conflict with each other. In order to effectively stop ions inside a multipole, a sufficiently high gas density is usually needed, and for high selectivity of isolation of selected ions or excitation of resonant ion oscillations and their heating (for fragmentation and other transformations), the gas density should be relatively low.

One of the possible approaches to overcome this contradiction by creating a slightly diverging supersonic gas flow [24] directed along the multipole axis and creating an increased gas density near this axis is described in our patents in the Russian Federation [25-27]. When using a multichannel supersonic flow directed along the generators of a slightly diverging wedge, as described in our patent application [28], the sensitivity can be noticeably higher than with a single channel of the same flow. In this case, the residence time of ions inside the flow in the multichannel case can be significantly reduced, and at the end of the quadrupole, the analyzed ions can be focused near the axis of the radio frequency quadrupole, where the gas density will be close to the residual density. Thus, the problem of the extraction of ions from the gas stream, critical for its propagation along the axis of the quadrupole, can also be practically eliminated.

The software for the analysis of experimental data should include software packages that basically implement the original methods developed by us, described in [29–33]. Among these methods, the most important are:

1. The correction method for the effects of saturation and "dead" time when using time-to-digital conversion for recording data of the VPMS [31];

2. A method for identifying target compounds based on selective digital filtering of a series of mass spectra recorded for specific time-varying flows of components of the analyzed mixture [30];

3. A method for identifying exponential contributions to a set of ion current curves, developed earlier for analyzing a set of effusiometric curves [32].

The use of a subsonic flow passing through a glow discharge zone to ionize the coaxial flow of a test gas sample at the inlet of a radio frequency quadrupole is described in [34]. The gas pressure in the ionization region of this sample is from 0.03 to 3 millibars, which is at least several hundred times higher than the residual gas pressure in the quadrupole in our case. The cross-section of the ionization region in our case is approximately 25 smaller with a comparable gas density in the ionization region, which in our case is not at the entrance, but inside the quadrupole. A significant increase in the sensitivity of the analysis in our case and a decrease in the load on the pumping system should be expected.

Dynamic methods of capturing ions in a quadrupole trap, when the reverse ion exit is blocked by switching on the corresponding potential (for example, at the input diaphragm of the quadrupole) until the launched ion packet returns from the pivot point, only a small part of the initial ion flux can be used if subsequent manipulations with the ions require relatively great time. The initial ion flow should be locked at this time, and the corresponding ions are usually lost.

The use of a rotational field for the selective dissociation of ions accumulated in a quadrupole linear trap in a collision with atoms or molecules of a buffer gas is described in US Pat. No. 7,351,965 B2 [35]. It is proposed that the registration of product ions, as well as the removal of unwanted ions, be made through gaps along the vertices of the main electrodes of a hyperbolic shape. It is proposed to compensate for violations of the quadrupole field near these slots with the help of thin electrodes located along the slots in the middle at the exit from them. When conducting dissociation, it is proposed to intentionally distort the quadrupole field by setting potentials on these auxiliary electrodes that are different from the potentials of the main electrodes. This is useful for shifting the resonance frequencies of strongly promoted ions to prevent their death on the quadrupole electrodes. In the considered patent [35], it is proposed to capture ions dynamically in the trap, raising the voltage at the input diaphragm, because the buffer gas pressure in the quadrupole is not enough to stop the ions reflected from the blocking potential in the last section of the quadrupole. In this case, ions remain in the trap, which have reflected from this potential and did not have time to go back through the output diaphragm of the quadrupole until a blocking voltage is established on it. In the patent [35], to ensure the capture of a sufficiently large number of analyzed ions, the use of a relatively long quadrupole (1000 mm) is assumed. This length not only increases the dimensions of the device, but also makes more stringent requirements for the parallelism of the rods of the quadrupole and other conditions for its manufacture to ensure uniformity of the resonant frequencies of free movements of ions in different places of the quadrupole. The ion accumulation method of the present invention is expected to accumulate a sufficient number of ions in a quadrupole, an order of magnitude shorter, with a comparable residual pressure of the buffer gas.

A standard method for estimating the cross sections for collisions of ions moving in a gas is one or another type of measurement of the mobility of the ion or the proportionality coefficient between the stationary velocity of the ion and the electric field strength that causes this movement. Often this movement is used for preliminary separation of ions. Since in ordinary versions of the method, the time of movement of ions in a drift tube is relatively small, the most acceptable combination of separation of ions by mobility with a time-of-flight analyzer with orthogonal ion input.

A serious problem of this combination is the provision of high ion transmission through the drift tube in the HPMC. One of the possible solutions was proposed by us in US patent No. 6,992,284 [36], which provides a fairly detailed overview of the work on the separation of ions by mobility. Patent 6,992,284 refers to the use of a sequence of alternating sections of a strong and a weak field in a drift tube at a gas pressure of several Torr instead of a uniform electric field. This leads to the focusing of ions to the axis of the quadrupole and allows you to slightly increase the total voltage along the pipe, which favorably affects the resolution of ion packets in mobility. Nevertheless, in all realized variants of separation of ions by mobility, a sufficiently high resolution cannot be obtained. Even for ion drift at atmospheric pressure, a resolution of more than 100 is not achieved.

In the present invention, the mobility of the ions in their separation is realized when the solution flows through the capillary after an abrupt change in the direction of the electric field in the capillary. Essentially, this is some variant of capillary electrophoresis. As with motion in a gas, the mobility of an ion here is determined by the ratio of its charge to the collision cross section. The peculiarity is that in a solution the charge of an ion can vary depending on the properties of the solution, in particular its pH. For ions of biomolecules, it can even change its sign, and at the isoelectric point (with the corresponding pH of the solution) it is equal to 0 on average. Carrying out such capillary electrophoresis at various pH values of the solution, one can actually realize two-dimensional preliminary separation of the components of the analyzed solution, which includes and isoelectric point separation.

Usually, isoelectric separation and focusing of individual fractions of mixtures of biopolymers use electrolytes that are locally nonuniform in pH. Moving under the action of an applied electric field, most often close to uniform, the ions of biomolecules, reaching zones with a pH close to their isoelectric points, stop moving and accumulate in these zones. This separation method is not well suited for combination with mass spectrometric detection of the separated fractions. In the work of R.A. Zubareva and co-workers [37] described the design of a device for isoelectric focusing and separation of mixtures of peptides and proteins, working in conjunction with a mass spectrometer with an ion source based on electrospray of solutions. Their next work [38] described an improved version of such a device, designed to collect separated fractions. The principle of operation is close to just described. The design itself seems rather complicated. The capillary, in which isoelectric fractionation of ions is organized, is divided into 8 sections. They concentrate biomolecules with corresponding isoelectric points during the period of isoelectric focusing, when an electric field is created in the capillary, which is directed upstream of the ion source. Sections are contacted with appropriate buffer solutions through Nafion membranes. When the field is turned off by the flow of the solution, the accumulated ion packets sequentially fall into the ion source and then into the mass analyzer.

In our proposed capillary ion source, fields of opposite directions are created in the inlet chamber of the source and inside the capillary. Such fields pass through the capillary only on average neutral ions, the isoelectric point of which coincides with the pH of the solution. By changing this pH by the gradual or simultaneous addition of a buffer solution, it is possible to provide access to the formation zone of the analyzed ions of biomolecules with different values of their isoelectric point.

U.S. Patent No. 7397029 of July 8, 2008, V.D. Berkut and V.M. Doroshenko [39], describes a method for exciting ion fragmentation by metastable excited particles (atoms or molecules). The initial ions are extracted using a primary mass spectrometer, while they accumulate in a three-dimensional or linear ion trap or move in a transport multipole. It is possible to additionally excite the initial ions or product ions by applying an alternating electric field to produce secondary product ions due to collisional activation. All of these resulting ions are recorded by a secondary mass spectrometer. Metastable atoms and molecules are supposed to be obtained using a gas discharge. They are supposed to be introduced into the ion trap in a direction perpendicular to the axis of the trap.

In our case, metastable atoms or molecules can be obtained in the ion source of electron ionization in a supersonic gas stream, and their density in the stream and distribution over the excitation energies can be controlled by changing the flow or energy of ionizing electrons. Moreover, when using a mixture of inert gases as a buffer gas, a change in the energy of the metastable atoms can be achieved by changing the energy of the electrons, which can allow selective ionization of the components of the analyzed sample without changing the composition of the buffer gas.

SUMMARY OF THE INVENTION

The features of the possible implementation of the proposed methods are: The flow of the studied ions is the result of the extraction of ions from a liquid sample leaving the capillary introduced into the radio-frequency quadrupole, or such ions are obtained from the molecules of the analyzed compounds in the gas phase due to recharging with buffer gas ions or Penning ionization by metastable atoms of a supersonic gas stream. The extraction of ions is stimulated by the action of a “heated” supersonic gas flow on the surface of the outgoing liquid. To ensure greater efficiency in using this stream to form the analyzed ions, the capillary is inserted into the channel of a larger diameter so that the output tip of the capillary is close, but does not extend beyond the end of the channel. There is a gap between the capillary and the inner wall of the channel for some length before the exit of the capillary. The exit from the channel is made so that the supersonic flow directed to the exit of the capillary, its main part falls into the channel. At the inlet end, the gap between the channel and the capillary is filled with an impermeable binder material. Metastable atoms and ions in the aforementioned flow are formed either in a high-frequency gas discharge organized at the outlet of the supersonic gas flow formation channel, or this flow is passed through an electron ionization source with a variable kinetic electron energy. The supersonic flow jet is directed to the output tip of the capillary and passes near the center of the input diaphragm into this quadrupole. The leakage of liquid through the capillary is determined by the pressure of saturated steam in the inlet chamber containing the analyzed solution, or by a specially organized differential pressure. The exit of the gas mixture through the capillary is provided by the pressure drop along the capillary, which is maintained constant. The analyzed gas mixture is injected into the inlet chamber once, or continuously using a syringe. To ensure a constant rate of gas outflow through the capillary during a single injection of the gas mixture into the inlet chamber of the capillary ion source, buffer gas is continuously introduced at a constant, for example, atmospheric pressure. The rate of leakage of the liquid sample can also be controlled by changing the temperature of the inlet chamber, creating the corresponding saturated vapor pressure in this chamber containing the analyzed solution.

The heating of the inlet chamber in the analysis of gas mixtures also plays an important role. The transition to a higher temperature of this chamber can lead to the observation of relaxation processes, which will carry additional analytical information about the analyzed compounds. A higher temperature will cause an increase in gas flow through the outlet capillary. This will lead to an initial increase in the recorded signal from the ionized components of the gas mixture. The consequence of this will be a redistribution of the density of impurity compounds inside the inlet chamber and subsequent relaxation attenuation of these signals with characteristic times specific to different compounds. The characteristic relaxation times of the intensities of the ion peaks corresponding to a particular compound will be determined by the diffusion coefficient of this compound and the adsorption capacity of this compound on the walls of the inlet chamber. Recording relaxation curves is also possible with decreasing temperature of the inlet chamber.

The increase or decrease in temperature in the inlet chamber requires noticeable time, and the relaxation attenuation of ion currents will occur after a new temperature level is established. Ion currents corresponding to certain compounds will look like unimodal peaks during sequential registration, the shape of which will be specific for different compounds under given measurement conditions. The detection of such peaks for the target compounds in the analyzed mixture can be carried out on the basis of our method of selective digital filtering by known mass spectra of these compounds [30]. The coincidence of the obtained peak shape with the expected for a given target compound will be a criterion for its detection, and the area of this peak will determine the relative content of this compound in the analyzed mixture. To quantify this content, it is advisable to preliminarily carry out appropriate calibration measurements when the desired target compounds are added to the test mixture in known concentrations.

For exponentially decaying “tails” of the obtained ion current distributions with different values of miz, the best in the rms transition matrix from the previous set of values of the mentioned ion currents to the next such set can be found. After calculating the eigenvalues and eigenvectors of the obtained transition matrix, we find the approximation of the mentioned “tails” of distributions acceptable by the expected error by a linear combination of the minimum number of the mentioned eigenvectors with exponential decay factors determined by the corresponding eigenvalues. We take the found set of such eigenvectors for the mass spectra of the detected components in the considered data set, and the calculated coefficients of the mentioned linear combination for approximate estimates of the relative contributions of these components to the analyzed mixture. These estimates can be tested and refined by conducting appropriate calibration experiments.

After passing through the electron ionization source or gas discharge zone, the jet of a supersonic gas stream, together with ions and metastably excited buffer gas atoms, enters the radio-frequency quadrupole. The braking longitudinal field organized in the first half of the quadrupole, combined with a relatively dense gas flow, leads to the accumulation of a significant number of buffer gas ions in this half of the quadrupole around its axis. The effective temperature of this ion cloud, as shown by our measurements, can be quite high (about 6000 K). This temperature can still be significantly increased due to forced oscillations or ion rotations. In this case, one should expect effective evaporation and crushing of droplets of solution leaving the capillary. This will occur both due to the transfer of energy from oscillating "heated" ions to the ions on the surface of the droplet, as well as their entry into the droplet and an increase in the charge density on this surface. These droplets, having passed through a cloud of oscillating ions of a buffer gas and pushed further by the space charge of these ions, will be partially picked up by the jets of the gas stream. Since their mobility is significantly less than the mobility of the buffer gas ions, they will be more entrained in the gas flow and more effectively displayed in the second half of the quadrupole.

If in this half the radio frequency voltage is much higher than in the first one, and it is chosen optimal for focusing relatively large ions of biomolecules, then the buffer gas ions will die here on the rods of the quadrupole. The analyzed ions emerging from the charged droplets will be focused to the axis of the quadrupole. In the absence of a longitudinal field in this half of the quadrupole and the presence of a sufficiently dense cloud of accumulated buffer gas ions, an electric field will appear in the first half of the quadrupole, which prevents the return of the analyzed ions to the first half of the quadrupole, and these ions will accumulate around the axis of the quadrupole. Under the influence of their space charge, the excess part of such ions will be output through the output aperture of the quadrupole to the mass analyzer. In this case, the under-evaporated droplets, having significantly higher m / z values than the analyzed ions, will be pushed out by the same space charge at relatively large distances from the axis of the quadrupole. These drops will thereby be subject to the repulsive field of the output diaphragm of the quadrupole. Holding inside the quadrupole, these droplets will be heated by the radio frequency field of the quadrupole and by the high-energy small ions leaving these droplets, and ultimately release the analyzed ions contained in them, which, after they are focused to the axis, will be detected in the mass analyzer.

After leaving the quadrupole, the ion beam is introduced into the subsequent mass analyzer using a coaxial conical or wedge-shaped skimmer with an inlet or slot at its apex. In this case, most of the gas stream is scattered by the outer surface of the skimmer and enters the first stage of differential pumping.

The features and advantages of the proposed approach are a consequence of the small divergence of a supersonic gas stream emerging from a relatively thin and long channel with a reduced (compared to atmospheric) gas pressure at their inlet. The mean free path of the molecules of the main component of the gas stream is comparable with the diameter of the channel. The conditions for the formation of the aforementioned flow can be selected so that in the radio-frequency quadrupole the density of the gas near its axis does not practically differ from the density of the residual gases at the periphery of the radio-frequency quadrupole. This density for the effective functioning of the electron ionization source should be sufficiently low, corresponding to a pressure at room temperature of 10 ^-4 Torr or less. Thus, the movement of ions near the axis of the quadrupole will be the same as in a conventional quadrupole with the same density of residual gases. The difference will be that the relatively energetic natural vibrations of the ions in the direction of displacement of the gas stream will be much faster offset by the gas stream at the beginning of the quadrupole. Thereby, more favorable conditions will be provided for recording the mass spectra of the sample under study in comparison with a vacuum quadrupole, a gas-filled quadrupole (a smaller gas flow to the mass analyzer) or in the presence of a supersonic gas jet along its axis (a larger ion flux to the mass analyzer).

If there are no electric fields in the inlet chamber containing the analyzed solution and inside the capillary of its outflow, then a survey mass spectrum will be recorded in the selected m / z range for these ionization conditions. If, in this chamber, a sufficiently strong voltage is created at the surface around the entrance to the capillary at a solution surface potential close to 0, then ions of the corresponding charge sign will accumulate around this capillary, and on average neutral molecules from the solution will mainly enter the capillary. Including it can be biomolecules, the isoelectric point of which is close to the pH of the solution. This situation is a consequence of the appearance of a reverse direction field in the capillary due to the relatively small potential at the capillary exit due to the contact of the accumulated buffer gas ions in the quadrupole with the cloud.

By switching the polarity of the blocking voltage, part of the accumulated ions at the entrance to the capillary will be launched inside the capillary. In accordance with their mobility under the influence of an electric field inside the capillary, these ions will move at different speeds and will be recorded by a mass analyzer in the form of packets separated by the exit time. After the release of the last package, registration of quasineutral molecules will continue. When the solution leaves the capillary, quasineutral molecules can change their charge state due to the penetration of buffer gas ions into the solution, and they can ultimately be registered in the mass analyzer. To prevent electrolysis of the analyzed solution on the electrodes of a capillary ion source, these electrodes can be coated with a thin dielectric film.

If an alkali metal salt, for example, sodium acetate, was added to the analyzed solution in a suitable concentration, then two-dimensional charge distributions of multiply charged ions of biomolecules by the number of protons held by these ions, and in this case sodium ions, can be observed. Using our developed method of decomposition of such charge distributions [33,40], it is possible to determine the probabilities of holding various charge carriers by separate ionogenic groups of biomolecules. If we measure the pH of the main solution and the concentration of sodium ions in it, then having obtained the probabilities of the proton and sodium ions being retained by certain sites of biomolecules at different pH or concentrations of sodium ions, we can estimate the ratios of the corresponding equilibrium constants for these sites. The totality of such estimates can characterize the spatial structure of a biomolecule in solution and practically does not depend on changes in the composition and type of ions upon transition to the gas phase and on their various discriminations during their transportation and registration.

With a significant change in the pH of the solution, for example, by adding the appropriate buffer solution, the composition of quasi-neutral molecules moving in the channels along with the solution can change. Those. in fact, it is possible to separate biomolecules in solution according to their isoelectric points. In combination with the above-described separation of ions by mobility at the outlet of the channels, this is an important advantage of the present invention.

In the analysis of neutral microimpurities in both a liquid and a gas medium, they are detected in the form of ions formed in the gas phase under the action of metastable atoms and ions of a supersonic gas flow. Here, some additional separation of the analyzed microimpurities is possible when the energy of ionizing electrons in the ion source of electron ionization changes. For this purpose, for example, a mixture of inert gases with close concentrations: He, Ne, Ar, Xe can be used as a buffer gas in the formation of a supersonic flow. The ionization energies of these gases and the formation of their metastable excited atoms vary in the range of about 10 eV and cover the range of possible ionization energies of most known compounds. The transition from one electron energy to another for an interval specific to a given target compound may allow the release of ions formed from this compound.

BRIEF DESCRIPTION OF ILLUSTRATIONS

For a more complete understanding of the present invention, the following description is related to the corresponding illustrations.

Fig. 1. General scheme of the gas-dynamic interface of the ortho-VPMS with a microchannel ion source and a supersonic gas source.

Fig. 2. Illustration for the preliminary separation of charged and quasineutral particles in a microchannel ion source.

Fig. 2a. Features of the functioning of a microchannel ion source in the analysis of neutral impurities in liquids.

Fig. 3. Schematic view of the cross-section BB, Fig. 1, the interface in the location of the region of evaporation of charged droplets and declusterization of the analyzed ions.

Fig. 4. Experimental dependences of the recorded ion currents for molecular and two fragmented cyclohexane ions (2% impurities in helium) on the radio frequency voltage in the quadrupole for room temperature (25 ° C) and increased (100 ° C) initial gas flow temperature.

Fig. 5. Experimental dependences of the recorded ion currents and their relations for molecular and two fragmented cyclohexane ions (2% impurity in argon) on the oscillating voltage for the existing interface with a displaced supersonic gas stream at a radio frequency quadrupole voltage exceeding the threshold for the passage of these fragmented ions through the interface.

Fig. 6. Arrhenius approximation of the relative intensity of fragments of oscillating cyclohexane ions at an average distance of about 1 mm from the supersonic argon stream at the found optimal temperature of molecular cyclohexane ions accumulated in the quadrupole of ~ 6000 K.

Fig. 7. Experimental dependences of the recorded ion currents and their relations for molecular and two fragmented cyclohexane ions (2% impurities in helium) on the oscillating voltage for the existing interface with a displaced supersonic gas jet at a radio frequency quadrupole voltage exceeding the threshold for the passage of these fragmented ions through the interface.

Fig. 8. Illustration to the formation of multidimensional relaxation data.

Figure 9. Dependence of the flux Q _{in of a} mixture of 2% Xe in Ar through a capillary on the pressure p _in at the inlet of the capillary: points are experimental data, the solid curve is an approximation by a quadratic function: Q _in ≈ a⋅ p _in ² .

All these illustrations are explanatory in nature and do not impose any restrictions on the possible implementation of the invention.

DETAILED DESCRIPTION OF THE INVENTION

A new approach for transporting ions from the high-pressure region at the exit of the mobility cell to the vacuum part of the mass spectrometer using a supersonic gas flow is described in our US patent No. 7,482,582 of January 27, 2009 [42]. It was further developed to provide additional analytical capabilities due to the resonant excitation of ion rotation [43] around a supersonic flow in our next US patent No. 7.547.878 of June 16, 2009 [44]. The specific development of these approaches to ensure effective quantitative determination of the presence of impurities in gas mixtures and structural analysis of multiply charged ions of biomolecules is described in our patents in the Russian Federation [25-27]. The implementation of a new version of the accumulation and isolation of the analyzed ions from an electronic ionization source in a radio frequency quadrupole based on the use of an off-axis multichannel supersonic flow is described in our patent application [28]. The jets of this flow are directed along the generators of the diverging wedge with the axis of symmetry directed along the axis of the radio-frequency quadrupole. In this case, in contrast to the version of the orthogonal ion output to the mass analyzer described in the RF patent [27], there is the possibility of efficient coaxial coupling of the mass analyzer with a gas-dynamic interface.

In the present invention, a jet of supersonic gas flow (5) from the channel (4), Fig. 1, is directed to the output tip of the capillary (89), passing near the midpoint of the input diaphragm (8-9). The action of atoms (including metastably excited ones) and ions from the jet (5) on the outgoing meniscus (91) of the analyzed solution from the capillary (89) of the microchannel source (82) stimulates the formation of solution droplets and the evaporation of the solvent. In order to make fuller use of the energy of the jet (5) for these purposes, the capillary (89) is placed inside the cylindrical channel (84) so that there is some gap (210), Fig. 2, between the outer wall of the capillary (89) for some extent in front of the outlet end of the capillary and the inner wall of the channel (84). In the area close to the upstream side of the capillary (89), the gap (210) is filled with an impermeable binder material (211). The outlet of the channel (84) is designed so that the main part of the jet (5) falls into the gap (210). Upon encountering obstacles within the gap, the jet (5) is randomized, forming a diverging flow (209) with a middle direction close to the direction towards the jet (5), contributing to the exit and evaporation of the solution from the capillary.

We carry out the necessary estimates when filtering aqueous solutions through a channel with a diameter of 10 μm and a length of 1.5 cm. The average thermal velocity of water molecules at room temperature - T _r = 293 K (k is the Boltzmann constant, M _H2O - water molecules) is equal to:

The pressure of saturated water vapor at room temperature is ~ 18 Torr, the equivalent density is n _sat , the channel radius is r = 0.5⋅10 ^-3 cm. The rate of liquid evaporation is equal to the rate of condensation under equilibrium conditions:

- из канала 10μ диам. Поток газа в нашей системе при остаточном давлении в интерфейсе 10^-4 Торр - 0,75 sccm ≈9,5 см³ Торр/с. Таким образом, поток паров воды из канала при комнатной температуре на ~2% увеличит остаточное давление в интерфейсе. Поток жидкости (масса в секунду, Ландау Гидродинамика, стр. 82) через канал радиуса r и длины L при перепаде давления Δр (~2.4⋅10⁴ дн/см² для давления насыщенных паров воды при комнатной температуре 18 Торр) и динамической вязкости v=0.01 см²/с для воды (Ландау стр. 74):

- from the channel 10μ diam. The gas flow in our system at a residual pressure in the interface of 10 ^-4 Torr is 0.75 sccm ≈9.5 cm ³ Torr / s. Thus, the flow of water vapor from the channel at room temperature by ~ 2% will increase the residual pressure in the interface. Fluid flow (mass per second, Landau Hydrodynamics, p. 82) through a channel of radius r and length L with a pressure drop Δр (~ 2.4⋅10 ⁴ days / cm ² for saturated water vapor pressure at room temperature 18 Torr) and dynamic viscosity v = 0.01 cm ² / s for water (Landau p. 74):

. Скорость истечения в объемных единицах (пара) будет Q≈0.04 см³ Торр/с.1 cm ³ Torr / s for water vapor at room temperature in the mass scale corresponds to -

. The flow rate in volume units (steam) will be Q≈0.04 cm ³ Torr / s.

Thus, for a channel with a diameter of 10 μ and a length of 1.5 cm, the evaporation rate at room temperature is ~ 5 times higher than the rate of water outflow at a pressure drop of 18 Torr. It is possible to increase the rate of solution outflow from the channel (89) by increasing the pressure in the inlet chamber (83) of the microchannel source, for example, by heating the chamber (83) (85). At 50 ° С in chamber (83), the pressure of saturated water vapor will be more than 92 Torr, and the outflow rate will exceed the evaporation rate at room temperature of the meniscus of the solution with its minimum area. At atmospheric pressure in chamber (83), the fluid flow by gas equivalent will be about 1.7 cm ³ / s or not more than 18% of the gas flow at 0.75 sccm. Thus, the outflow of the solution at atmospheric pressure in the inlet chamber with a gas flow of about 0.6sccm will provide an acceptable level of residual pressure of about 10 ^-4 Torr.

If 100% of the gas flow “works” to heat the solution in the channel (89), then at the initial gas temperature of about 100 ° Celsius the energy of gas atoms will be enough with about 6-fold supply to maintain the evaporation of water from the channel at room temperature. The stock becomes almost twenty times for evaporation at a temperature slightly higher than 0 ° C. Thus, freezing of the solution in the channel is hardly possible.

In addition to the aforementioned heating (85), the design of the capillary ion source suggests that the inlet chamber (83) is closed, for example, with a rubber gasket (87). A liquid sample is injected through this gasket using a syringe (88). In addition to the heating option (85), three more modes of operation of a capillary ion source are possible. In the first case, the syringe (88), containing a sufficient volume of the analyzed liquid sample, is left for the entire time of measurement, and the liquid from this syringe under the influence of atmospheric pressure on the syringe piston enters the chamber (83) of the source, maintaining a constant volume and composition of the analyzed sample in it . In the second mode of operation, a fixed volume of the liquid sample is started using the syringe (88), the syringe with the liquid is removed, and the syringe containing the inert gas medium is inserted. This “gas” syringe is left for the entire time of measurement, and it maintains a constant (near atmospheric) pressure of the gaseous medium above the liquid sample, allowing it to dissipate by seepage through the capillary (89). The last option is that after entering a fixed volume of the liquid sample, as in the second mode, instead of a “gas” syringe, a syringe (88) is inserted containing a buffer solution with a pH significantly different from the initial pH of the solution in the chamber (83). If you control the ionic composition of the analyzed solution (the methods and equipment for this are known - http://www.shelfscientific.com/cgi-bin/tame/newlaz/microionn-m82.tam?ofr=16544039), then you can record the distribution of multiply charged ions of biomolecules in these changing and well-known conditions. We carry out the decomposition of the obtained multidimensional charge distributions (in the presence of several charge carriers in the solution that can be retained by biomolecules) according to the technique described by us [33]. Next, we establish the adequacy of the changes in the probabilities of the determined probabilities of carrier retention by individual ionogenic groups of the biomolecule to the equilibrium processes in solution. In cases of correspondence to equilibrium relations for such groups, the corresponding equilibrium holding constants of various charge carriers can be determined that are specific for particular conformations of the studied biomolecules in solution. Thus, they can be used to characterize such forms in the analyzed mixtures. Here, the problem may be the rate of establishing the acceptable uniformity of the composition over the entire volume of the solution and the correspondence of the measured concentrations of charge carriers to those that actually determine the replacement processes of these carriers for certain ionic groups of the studied biomolecules.

Charged droplets and cluster ions emerging from the capillary (89) under the action of a focusing radio-frequency energy enter the zone of accumulated ions (206) of the buffer gas from a supersonic jet (5). Under the influence of sufficiently energetic collisions with these ions (their measured temperature can be around 6000 K - Fig. 6), further evaporation of the droplets and declustering of the ions occur. Under the action of the space charge of ions (206) and flow (5), under-evaporated droplets and cluster ions pass into the second half of the quadrupole (10). The radio-frequency quadrupole voltage here is set so that the buffer gas ions from the first half of the quadrupole lose their motion stability and die on the rods of the quadrupole. In this case, heavier analytical ions (304), Fig. 3, they are focused towards the axis of the quadrupole, and their volume charge eject the under-evaporating droplets (308) with large m / z into orbits more distant from the axis of the quadrupole. Subjected to stronger repulsion of the field (39) of the output diaphragm (19), these droplets (12) will remain inside the quadrupole for a sufficient time, being heated by the action of the radio frequency voltage of the quadrupole and collisions with ions and residual gas atoms to extract analytical ions (20) that will ultimately enter through the diaphragm (19) and the system of focusing electrodes (17) in the form of a packet of registered ions (70) into the transport and registration system of the ortho-VPMS.

The gas-dynamic interface, schematically and shown in Fig. 1, in the main parts is close to the option given in the application [28]. A distinctive point from this application is that the gas stream (1) already does not contain the analyzed compounds that are blown through the valve (53). In this case, a mixture of inert gases (He, Ne, Ar, Kr, Xe) is formed in chamber (2) at a lower pressure than atmospheric pressure (He, Ne, Ar, Kr, Xe) in close concentrations so that in the electron ionization source (6) it is possible to obtain various ions by changing the electron energy and metastable atoms of said inert gases. The transition from one electron energy to another for an interval specific to a given target compound may allow the release of ions formed from this compound. The desired initial temperature of these gases is maintained by passing current through the winding (3). Heating only the input tip of the channel (4) is sufficient to provide increased kinetic energy of the atoms of the jet (5), because the formation of this jet occurs at a relatively small distance from the beginning of the channel. For the channel diameter of about 0.2 mm for our measurements [24], this distance does not exceed 4 mm, then the gas atoms are mirrored from the channel walls, practically not exchanging energy with them.

This behavior of the gas flow is confirmed by our measurements shown in Fig. 4. The measurements were carried out for a gas mixture with a content of 2% cyclohexane in helium for the interface with a displaced gas stream, shown in the diagram on the right (404). The graph in the upper right shows the dependences of the ion currents of the molecular ions of cyclohexane with m / z = 84- (401) and its fragmented ions with m / z = 69- (402) and with m / z = 56- (403) on the radio frequency voltage at lack of heating of the channel tip (3), the initial gas temperature is 25 ° C. The distribution of the potential (405) of the longitudinal field along the axis of the quadrupole is shown in the diagram on the right. The oscillatory nature of the obtained dependences is due to the natural vibrations of ion clouds in the focusing radio frequency field of the quadrupole. The graphs at the top left show the dependences of the same ions when heating (3) the tip of the channel (4) to 100 ° C. One can see an approximately twofold drop in the initial values of the molecular ion current (406) and a more than threefold increase in the ion current with m / z = 56 (407), and a relatively small increase in the ion current with m / z = 69 (408). This behavior can be explained by a decrease in the gas density in the jet upon heating and a corresponding weakening of the stabilization of molecular ions and their increased decay. These relatively small ions, focusing around the quadrupole axis, will push molecular ions with their space charge to a sufficiently large distance from the axis of the quadrupole and lead to their fragmentation and the formation of new fragment ions. That is, the process accelerates itself and leads to the observed significant increase in the current of fragmentary ions. If the dependencies in the upper half of Fig. 4 were obtained with a relatively small ionizing voltage of 12V, the graphs at the bottom left (curves (409) - m / z = 84, (410) - m / z = 56, (411) - m / z = 69) show a further significant an increase in the relative intensity of fragmentary ions with an increase in ionization energy to 40 eV while maintaining the heating of the channel tip (4) to 100 ° C. This behavior confirms the described mechanism for accelerating the decay of molecular ions, since the increased energy of ionizing electrons increases the initial fragmentation, which makes the cascade of the described processes even more effective. The observed approximately 4-fold excess of the ion flux with m / z = 56 compared to molecular ions differs noticeably from their fraction of 0.7 from the same ions with m / z = 56 for the mass spectrum from the database of the National Institute of Standards ( 412) obtained for an ionization energy of 70 eV.

For the entire system to function properly, the gas flow (5) must be such that the density of the gas flow near the axis of the quadrupole when leaving it is so small that the inlet (70) of ions with gas through the skimmer (71) does not lead to an unacceptable residual pressure inside mass analyzer. Since the gas flow diffusely scatters (81) on the skimmer (71), pumping (75) will be less efficient than for the case of orthogonal ion removal [27]. Thus, when the mass analyzer is coaxially coupled with a gas-dynamic interface, it is necessary to use more powerful pumping, or confine oneself to the inlet of less intense gas flows to ensure the operability of the ion source (6). In this case, the contribution of the flow from the capillary must also be taken into account (89). If, when injecting an aqueous solution according to the above estimate, this contribution does not exceed 18% of the maximum possible flow (5) at atmospheric pressure inside the chamber (83), then for the inlet of gas mixtures the estimate of the flow from the capillary (89) is even lower (almost three times for argon flow as a buffer gas).

, когда кинетическая энергия направленного движения его атомов становится равной половине исходной тепловой энергии этих атомов. Здесь и далее k - постоянная Больцмана, Т₀ - исходная температура газа, М - масса атомов газа. Для аргона и комнатной температуры (293 K) эта скорость равна:An upper estimate of the expected gas flow from the capillary (89) can be obtained on the basis of our proposed model for the formation of a supersonic jet [24] and our measurements. In this model, the critical role is played by the critical flow rate.

when the kinetic energy of the directed motion of its atoms becomes equal to half the initial thermal energy of these atoms. Hereinafter, k is the Boltzmann constant, T ₀ is the initial temperature of the gas, M is the mass of gas atoms. For argon and room temperature (293 K), this speed is equal to:

Before reaching this speed, the dependence of the gas density n in a channel of radius r on the distance Z from the channel beginning with diffuse reflection of gas atoms from its walls in a first approximation is determined by the expression (the solution of equation (1) in [24]):

Z(n) достигает максимального значения и далее начинает убывать, указывая на то, что упрощенная модель течения газа в канале, основанная на балансе импульсов атомов газа в тонком слое газового потока, перестает быть адекватной. Она не учитывает, например, вклад диффузии атомов газа, что принципиально важно вблизи критической точки. Введение диффузионного члена в уравнение газового потока (уравнение (3) в [24]) позволяет пройти критическую точку

, но требует для получения осмысленного результата фактического отсутствия или очень малого сопротивления потоку в оставшейся части канала. Это условие может быть удовлетворено, если доминирующим здесь станет зеркальное отражение атомов от стенок канала, что представляется вполне вероятным для очень малых углов столкновения атомов со стенкой (при относительно большой продольной скорости этих атомов). Для проведенных измерений с каналом с диаметром 0.215 мм и величине потока F=0,75 sccm плотность потока такова:where n ₀ is the density of the gas at the entrance to the channel, f = nV _Z is the density of the gas flow in the channel, V _Z is the velocity of the gas flow. For

Z (n) reaches its maximum value and then begins to decrease, indicating that the simplified model of gas flow in the channel, based on the balance of momenta of gas atoms in a thin layer of a gas stream, ceases to be adequate. It does not take, for example, the contribution of the diffusion of gas atoms, which is fundamentally important near the critical point. The introduction of a diffusion term into the gas flow equation (equation (3) in [24]) allows one to pass the critical point

, but requires to obtain a meaningful result of the actual absence or very small resistance to flow in the remaining part of the channel. This condition can be satisfied if the mirror reflection of atoms from the channel walls becomes dominant here, which seems quite probable for very small angles of collision of atoms with the wall (at a relatively large longitudinal velocity of these atoms). For measurements with a channel with a diameter of 0.215 mm and a flux of F = 0.75 sccm, the flux density is as follows:

The distance to the critical point, based on (99), will be about 4 mm:

The relative resistance to gas flow with a mean free path comparable with the radius of the channel, which is determined mainly by the ratio of the lateral surface area (with a length of about the mean free path of gas atoms) to the cross-sectional area, is inversely proportional to this radius. Therefore, the density of the gas stream at a given initial pressure will be approximately proportional to the radius of the channel. Those. in the case under consideration, the flow through the channel with a diameter of 10 μm (proportional to the cube of the diameter) at a constant initial pressure will decrease by about 9940 times compared with the channel with a diameter of about 0.215 mm. An increase in the initial pressure to atmospheric pressure by a factor of ~ 25 compared with the initial pressure (30 Torr) will increase this flow approximately quadratically by ~ 625 times, i.e. the flux reduction factor for the channel (∅10 μm) will be about 16. Thus, for argon, the flow through the capillary (89) at atmospheric pressure in the chamber (83) will be about 6% of the 0.75 flow seem from channel (4) under the conditions of measurements. For helium from chamber (83), measurements show that the flux increase (compared to the argon flux from channel (4)) will be about 1.4 times, i.e. it will be no more than 9% of the total flow, which is also quite acceptable. Quadratic dependence (902), Fig. 9, the flow rate from the initial pressure was confirmed by us with experimental measurements for the supersonic jet formation channel currently used in our system. These data (901) indicate that the flow velocity at the entrance to the channel in our case is proportional to the initial pressure. Since the gas density is also proportional to pressure, this is precisely where the quadratic dependence of the flow value or flow density on pressure arises. Thus, based on (99), the distance to the critical point will decrease inversely with the initial gas pressure. This is qualitatively understandable, since the gas acceleration along the channel is proportional to the number of atomic collisions in the volume (or pressure squared) and inversely proportional to the gas density (the mass of the accelerating gas) will result in proportion to pressure. Thus, the flow velocity will reach a critical value at a distance from the channel beginning inversely proportional to the pressure. If for our channel (∅215 μm) the critical velocity was reached at a distance of about 3.6 mm from the entrance to the channel, then for a channel with a diameter of 10 μm and a pressure ~ 25 times greater than the critical channel, the critical length will be about 0.14 mm . Thus, the length of such a channel of 1.5 cm will be more than sufficient for the development of a supersonic flow in it if there were a vacuum at the outlet. The presence of some pressure at the outlet of the capillary can only reduce the magnitude of the flow through it. It can be expected in our case that the supersonic character of the gas flow from the capillary (89) will be preserved, despite the fact that near the outlet end of the capillary (89) one can expect gas pressure at the level of tenths of a Torr. The point is, to provide 16 times less flow from a capillary with a cross-sectional area of ~ 400 less than for channel (4), the flux density from capillary (89) should be ~ 25 times higher than from channel (4). If in the latter case for a 0.75 seem stream this density corresponded to a gas pressure at room temperature of ~ 0.6 Torr, then for capillary (89) it will be 15 Torr. Such a flow almost does not feel the presence of gas at a pressure of tenths of Torr near the end of the capillary (89). Only a small fraction of the gas from the stream (89) will experience collisions with atoms of the external gas, and this small fraction will leave the stream.

Thus, it can be expected that at the same pumping rate, the pressure of the residual gases in the proposed system at atmospheric pressure in the inlet chamber of the ion source (83) will be close to that in the existing gasdynamic interface - about 10 ^-4 Torr for the initial pressure in the chamber (2) ~ 30 Torr. To do this, it is necessary to slightly reduce the gas pressure in this chamber: when injecting an aqueous solution, this pressure should not exceed 25 Torr, and for a gas sample it can be about 28 Torr. As in the existing interface, a conical skimmer (71) with an inlet with a diameter of ~ 2 mm on the axis of the quadrupole will pass an admissible gas flow into the mass analyzer to provide a pressure of less than 10 ^-7 Torr in the mass analyzer, if the interface has the same pumping speed is ensured by a pressure no worse than 10 ^-4 Torr. In this case, the recorded ions (20) at the end of the quadrupole should be concentrated in this zone near the axis (38) and the electric fields (31), (33) and (35) should be accelerated to the energy φ, and the potential distributions convex upward (55) and (76) along the axis of the quadrupole, creating a focusing distribution of the potential in the plane orthogonal to the axis, directed inward to the skimmer (71). These fields are created by an electrode system (17). The value of potential φ (55) should be close to optimal for registration with ortho-VPMS. The increased value of the holding potential (59) at the output diaphragm (19), which creates the field (39), can be set for the accumulation of ions inside the quadrupole (10). Excitation of nonresonant ion oscillations (304) with a frequency significantly lower than the resonant frequency of the selected ions allows us to limit the range m / z of the accumulated ions. Cutoff of ions with relatively small m / z can be carried out by increasing the radio frequency voltage (302), which leads to loss of stability of motion and the death of ions with m / z, less than the specified value. Ions with relatively large m / z have a large amplitude of nonresonant oscillations as they approach the resonance and will more effectively die due to diffusion on the rods of the quadrupole (301).

The ion source of electron ionization (6) has an indirect heating cathode (18) (22), which provides a relatively small spread (at the level of 0.1 eV) over the controlled energy of ionizing electrons, which allows one to set the composition of ions and metastable excited atoms with good accuracy in the gas stream and to prevent significant formation of ions, the presence of which can lead to the death of metastable atoms. This is how the data shown in Fig. 7.

Under the action of electric fields (28) and (29) directed through an inlet diaphragm consisting of conductive layers (9) with non-conductive layers (8) between them, with a round inlet (48), ions are inside the gas stream and partially from its outside will be inserted inside the radio frequency quadrupole (10). By creating in the first half of the quadrupole a longitudinal electric field (13) directed against the flow (5) (counterfield), the flow of some ions into the second half of the quadrupole can be stopped. First of all, these will be ions moving outside the gas flow, the kinetic energy of which, when entering the quadrupole, will not allow overcoming the voltage drop in the first half of the quadrupole (56) - (60), shown on the potential curve (57) - (27) of the gas-dynamic interface, conducted near the electrodes on which the corresponding potentials U are given.

Ions moving inside the gas stream (5) will be inhibited not by the voltage drop, but by the electric field strength. In order to prevent the reverse exit of inhibited ions through the input diaphragm (9), a potential barrier is created on it (61). It also makes sense, as in our patent of the Russian Federation [41], to partition the inner surface of the entrance diaphragm (9) of the quadrupole (in section AA, Fig. 1) and apply sufficient but not too much to the adjacent sections (46) - (47) high radio frequency voltage in opposite phases. The accumulation of ions in the existing interface with a displaced supersonic jet was confirmed by observing the corresponding relaxation curves [19]. The data shown here in Fig. 4, if we take into account the above interpretation, they also confirm the significant accumulation of ions in our interface and, moreover, their significant heating, leading to a significant fragmentation of the accumulated molecular ions of cyclohexane.

Direct confirmation of such fragmentation is demonstrated by the data shown in Fig. 5. These data were obtained for a mixture of argon with 2% cyclohexane, passed as a supersonic gas jet through an ion source with an ionizing electron energy of 40 eV, at a radio frequency voltage of 40 V in a quadrupole, at which only molecular cyclohexane ions with m / z = 84 could go through the quadrupole. Nevertheless, in addition to these ions, fragmentary ions with m / z = 56 and m / z = 69 were also detected, which could form after a quadrupole from excited or “heated” ions with m / z = 84. The degree of additional heating of these ions or their additional effective temperature was set by applying a non-resonant oscillating voltage with a frequency of 50 kHz (more than half the resonance frequency for ions with m / z = 84) in two directions: in the direction of the gas jet displacement (vertical oscillations) and in orthogonal direction (horizontal oscillations). Such a significant shift of the frequency from the resonance gives an almost unambiguous correspondence between the amplitude of the oscillating voltage and the amplitude of the considered ions, regardless of the frequency of collisions with gas atoms and other ions. In accordance with our model of heating of ions during their motion in a gas under the action of an electric field [45], in this case there is an unambiguous relationship between the oscillating voltage and the additional effective temperature of the cyclohexane molecular ions.

The scale of this temperature is shown at the top of the graphs in Fig. 5. Curve (501) shows a decrease in the flux of detected molecular ions of cyclohexane with an increase in the amplitude of the oscillating voltage for vertical oscillations. The maximum of this voltage corresponds to the amplitude of oscillations of these ions of about 1 mm. Curves (502) and (503) describe the behavior of the flows (with a 20-fold increase) of the recorded fragmented ions with m / z = 56 and with m / z = 69. These curves are proportional to each other with good accuracy. Further, both sets of these two ions are analyzed in total. The total curve for them normalized to the coincidence of the initial values with the curve (501) is shown by contour circles (504). The ratio of the values (504) and (501) is shown on the curve (505). Close data were obtained in this case for horizontal oscillations. Curve (506) represents averaged values similar to (505) for vertical and horizontal oscillations. A noticeable decrease in noise oscillations is seen for curve (506) as compared with values (505).

It is more correct for kinetic calculations to use the ratio of the fluxes of registered ions with m / z = 56 and with m / z = 69 to the total sum of fluxes of all three considered ions with m / z = 84, m / z = 56 and m / z = 69. The Arrhenius approximation of this ratio from the assumed inverse absolute temperature of the molecular ions of cyclohexane is shown in Fig. 6 The value of the constant contribution to such a temperature, which turned out to be about 6000 K, was found from the minimization of the approximation error of the logarithms of the recorded values of the ratio under consideration (601) by the linear function (602). The value of the resulting activation energy turned out to be 1.33 ± 0.04 eV, and the frequency factor - (0.77 ± 0.07) × 10 ⁴ . The first value turned out to be quite reasonable for the processes of fragmentary ion formation: ⋅CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ ⁺ → СН2 = СН2 + ⋅CH ₂ CH ₂ CH ₂ CH ₂ ⁺ (m / z = 56) and ⋅CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ ⁺ → ⋅CH ₃ + CH ₂ = CHCH ₂ CH ₂ CH ₂ ⁺ (m / z = 69). The second corresponds with acceptable accuracy to the number of collisions of molecular ions with residual gas atoms at a pressure of 10 ^-4 Torr. The results obtained indicate that the accumulated ion ensemble is quite strongly heated; its basic temperature of 6000 K corresponds to an average ion energy of ~ 0.74 eV. In oscillations with an oscillation amplitude of about 1 mm, the temperature of the ion ensemble rises to 8700 K, which corresponds to an average ion energy of about 1.07 eV. This means that drops of the analyzed solution in the medium of such ions will acquire an excess charge. So, to charge a droplet with a diameter of 10μ to 1 V, approximately 3⋅10 ³ charges are needed on its surface.

Fig. 7 shows data similar to those shown in Fig. 5, when helium is the main gas in the supersonic jet instead of argon. If data with argon were obtained at an electron energy (40 eV) in the source (6) exceeding the argon ionization energy (15.76 eV), then in the case of helium the electron energy (20 eV) is significantly lower than the helium ionization energy (24.59 eV). At the same time, an electron energy of 20 eV is sufficient for the formation of metastable excited helium atoms. In the case of argon, no noticeable difference was observed for the observed dependences of the ion currents on the oscillating voltage for horizontal and vertical oscillations. However, for helium, the ratio of the currents of molecular cyclohexane ions for vertical and horizontal oscillations (705) has a pronounced minimum for oscillations with an amplitude of about 0.9 mm, which corresponds to the average distance of the supersonic stream from the axis of the quadrupole. A natural explanation for this is the additional loss of molecular ions in their collisions with metastable helium atoms in the jet. In the case of argon, since the electron energy was sufficient for the formation of argon ions, these ions could significantly reduce the concentration of metastable argon atoms in the jet due to their death during polarization capture of these atoms by argon ions. Therefore, a noticeable additional loss of molecular ions of cyclohexane (701) on metastable argon atoms was not observed in this case. In the case of helium, the normalized total curve (704) for fragmented cyclohexane ions with m / z = 56 (702) and with m / z = 69 (703) does not show deviations from the curve (701) growing with oscillating voltage, unlike the data with argon . This behavior confirms that for collisions with helium atoms, the increase in the effective temperature of ions during their oscillations is much less, as predicted by our model [45], than in collisions with argon atoms. However, the question arises of why there is no significant difference in the relative intensities of fragmentary ions for flows with helium and argon in the absence of forced nonresonant oscillations. A possible explanation for this effect is the accumulation of a sufficiently large ensemble of ions, when ion-ion interactions significantly exceed ion-atom collisions. When the oscillating voltage is turned on, since the ensemble of accumulated ions in this case is a homogeneous ensemble of molecular cyclohexane ions (the remaining ions with smaller m / z die on the quadrupole rods at a given radio frequency voltage), then in accordance with the theorem on the motion of the center of inertia, this ensemble oscillates as a single whole. Its additional kinetic energy of such oscillations is converted to an additional effective temperature precisely when it collides with gas atoms, not ions, since the relative (non-thermal) ion velocity during such oscillations remains unchanged on average.

This conclusion about the prevailing effect of the ensemble of accumulated buffer gas ions under the considered conditions on relaxation processes, including the analyzed ions, is very important for the present invention. In this case, the focusing of such ions in the quadrupole does not require the use of additional jets of a supersonic gas flow, except for that directed at the exit of the capillary (89). This greatly simplifies the entire structure. Such a fairly dense ensemble of relatively small buffer gas ions allows one to expect a rather high ionization efficiency of the studied compounds in gas mixtures and upon evaporation of such compounds from liquids. Analytical ions, as a rule, possessing larger m / z than the buffer gas ions, will be pushed out by the space charge of these relatively small ions to a sufficient distance from the axis of the quadrupole. Subjected for this reason, and also because of the increased collision cross section, to a greater acceleration from the atoms of the gas stream (5), analytical ions will more efficiently exit into the second half of the quadrupole (10) and then be registered in the ortho-VMS. This will also be facilitated by an increase in the radio frequency voltage in the second half of the quadrupole to a value leading to the death of buffer gas ions in this half and the presence for this reason of a mass flux of buffer gas ions from the first half of the quadrupole to the second. Such a flow will cause a difference in the density of the space charge of ions upon transition from the first half of the quadrupole to the second and the appearance of the corresponding electric field, which moves the analytical ions to exit the quadrupole and focuses these ions to the axis of the quadrupole. A sufficiently high effective temperature of the buffer gas ions in the accumulated relatively dense ensemble will also contribute to the evaporation and fragmentation of solution droplets, as well as the declustering of multiply charged ions of biomolecules. These processes can also be facilitated by forced oscillations or rotations around the axis of the quadrupole of the ensemble of accumulated buffer gas ions.

The recorded signal for a certain type of connection at a constant gas or liquid flow rate through the capillary (89) without external connection of this compound to the chamber (83) and while keeping the total volume and pressure of the gas or liquid in the chamber (83) constant will decay exponentially with some characteristic time. This will take place, at least starting from sufficiently low concentrations of this compound, when there are no nonlinear adsorption effects, and the outflow rate is low compared to the rate of establishment of adsorption and diffusion equilibrium in the chamber (83). If among these compounds there are those that produce ions with coinciding m / z values (or indistinguishable for a given mass analyzer), a sum of exponentially decaying curves with different, generally speaking, characteristic times will be observed. If such a total curve is divided into exponential components, then they will correspond to ions for various compounds.

It must be borne in mind that for each type of compound, as a rule, a whole spectrum of ions will be recorded, due to their interaction with ions and metastable excited particles of the main components of the gas stream. The relaxation curves for fragmented ions leaving together with molecular ions of compounds of a certain type will be exponentials with the same characteristic time as for a molecular ion. For several types of joints, these curves will be combined, for example, as shown in Fig. 8. Unique fragmentary ions of different origin (800) and (803) fall in their exhibitors (801) and (804), respectively. Fragmented ions (805), having contributions originating from both types of molecular ions, include two exponentials in their relaxation curve. In this case, it is possible to use multidimensional methods for separating the set of relaxation curves described, for example, in our patents in the Russian Federation [25,26] and in [32]. Time-spaced measurements for a constant interval Δt (802) of the peak intensity of the mass spectrum J _k (t + Δt) are written as the product of the transition matrix A _kl by the vector of previous intensities J _k (t) - equation (807):

Here l and k number the measured mass spectral peaks (the total number is n).

и собственные числа:The matrix elements of the transition matrix can be calculated using the least squares method from the condition of the best in the mean-square fulfillment of equality (807) for all moments of measurement. For this, the number of recorded mass spectra (measurement times) should be no less than the number of peaks of the mass spectrum (n). By solving the eigenvalue problem (809) for the transition matrix, eigenvectors are found

and eigenvalues:

описывают распределения интенсивностей ионов или масс-спектры для каждого исходного соединения, которому соответствует собственное число (808), являющееся экспоненциальным фактором затухания числа этих ионов. После того, как масс-спектры исходных соединений и экспоненциальные факторы затухания или релаксации соответствующих сигналов, могут быть вычислены вклады масс-спектров во всех зарегистрированных отсчетах общего масс-спектра в последовательные равноотстоящие моменты времени решением соответствующих систем линейных алгебраических уравнений, исходя из требования минимума среднеквадратичной ошибки приближения. Таким образом, могут быть получены масс-спектры для каждого исходного соединения и их вклады в общий масс-спектр, как в случае их полного разделения перед измерениями. Эти оценки могут быть протестированы и уточнены путем проведения соответствующих калибровочных экспериментов.Custom vectors

describe the distribution of ion intensities or mass spectra for each initial compound, which corresponds to an eigenvalue (808), which is an exponential decay factor of the number of these ions. After the mass spectra of the starting compounds and the exponential decay or relaxation factors of the corresponding signals, the contributions of the mass spectra in all recorded samples of the total mass spectrum to successive equally spaced time instants can be calculated by solving the corresponding systems of linear algebraic equations based on the requirement of a minimum mean square approximation errors. Thus, mass spectra can be obtained for each starting compound and their contributions to the total mass spectrum, as in the case of their complete separation before measurements. These estimates can be tested and refined by conducting appropriate calibration experiments.

To effectively use the described approach in real analytical measurements, it is necessary that the characteristic decay times of the recorded signals be in a range convenient for measurements. In the analysis of gas mixtures, the above estimate of the rate of discharge from the capillary (89) at atmospheric pressure in the chamber (83) was about 45 mm ³ / min for argon and about 67 mm ³ / min for helium. For a chamber volume (83) of about 46 mm ^{3, the} characteristic expiration time of a non-adsorbed compound with a sufficiently large diffusion coefficient will be about 1 min for argon and about 41 s for helium. If the increase in this time associated with adsorption and diffusion does not exceed 1 min, then it will be quite convenient for measurements.

Although for a liquid the velocity of outflow from the capillary (89), recalculated into the gas volume, turned out to be more than twice as much as for gas, the effective volume of the chamber (83) turned out to be too large in this case (for liquid it is approximately 1000 times greater for gas). Thus, when the chamber (83) is completely filled with liquid, the expected characteristic expiration time of the analyte is approximately 500 times higher than for gas. The way out of this is illustrated in Fig. 2a. If the volume of the analyzed liquid (214) is reduced by a factor of 50 to ~ 1 mm ³ , then the corresponding characteristic time will be about 10 minutes, which is less convenient than 1 minute, but also acceptable. To keep this volume constant, a syringe (88) containing a buffer solution is inserted through the rubber cover (87) into the chamber (83) so that its needle (212) enters the volume (214). The piston (213) of the syringe (88) is open to the atmosphere in the room, and if the atmospheric pressure in the room during measurements can be considered constant, the volume (214) will practically not change. The chamber surface (83), which is accessible for adsorption from the liquid and from the gas phase of the analyzed compounds, remains unchanged, which should lead to the constant contribution of adsorption and diffusion processes to the characteristic relaxation times of the corresponding signals. The consequence of this will be the applicability of the described approach to the analysis of multidimensional relaxing data for this case.

In order to bring the adsorption and diffusion contributions of the analyzed compounds to the measured characteristic times to a convenient range, heating (85) of the chamber (83) can be used. Each target compound has its own optimum temperature or temperature range that is most suitable for determining this compound. When approximately half of the molecules of this compound are stationary in the chamber volume (83), and the second half is adsorbed on its walls, the characteristic expiration time of this compound doubles compared to the case of the absence of adsorption if the diffusion rate is much higher than the expiration rate. At significantly lower temperatures, this characteristic time becomes too long, and the quasistationary concentration of the compound in question in the chamber (83) is greatly reduced, and the recorded ion currents for this compound are also significantly reduced. At high temperatures, the contribution of adsorption to the characteristic expiration time disappears. The value of this contribution, as was shown by us for the case of effusiometric measurements [29], depends exponentially on the adsorption energy of the compound in question divided by the surface temperature. Those. this value can be significantly different for different compounds.

With an abrupt increase in the heating power (85), it takes some time for the temperature in the chamber (83) to reach a new stationary level, during which the recorded ion currents will increase and, after passing the maximum values, will relax to 0 with characteristic times specific for different compounds. Also specific for each compound may be the initial growth rate, localization, and maximum values of the corresponding ion currents. If similar measurements were carried out in advance for a given target compound, then it becomes possible to detect the presence and estimate the relative concentration of this compound in the analyzed mixture based on the previously developed method of selective digital filtering [30].

, максимально подавляющий в среднем наборы ионных токов G_μk в этом двумерном массиве со всеми номерами k при заданном подавлении масс-спектра целевого соединения J_μ. Т.е. решается задача на условный экстремум - найти такие F_μ, которые дают минимально возможное значение дляSelective digital filtering includes the following steps. After registering the described array of ion currents over all peaks of the mass spectrum with the selected values μ = m / z, a linear digital filter F _μ is constructed with a single sum of squares of the filter coefficients

, which suppresses on average the sets of ion currents G _μk on _average in this two-dimensional array with all numbers k for a given suppression of the mass spectrum of the target compound J _μ . Those. the conditional extremum problem is solved - to find those F _μ that give the minimum possible value for

where F _trans is the transparency of the filter, showing the degree of attenuation of the resulting signal for the analyzed mass spectrum compared to the sum of the intensities of all its lines. This value is key to quantifying the relative share of the determined component in the analyzed mixture.

The formulated problem can be solved by minimizing the corresponding Lagrange function:

The values of the parameters λ and η can then be found using expressions for the corresponding conditions (813). After equating the 0 first derivatives with respect to the values F _{μ of} function (814), we obtain the following system of linear algebraic equations:

, F_eff=1/λ, θ=-η/λ. Величина F_eff может быть названа эффективностью фильтра, так как она связана со способностью фильтра подавить компоненты G_μk (для F_eff=0 величины F_μ=θJ_μ не зависят от набора G_μk). Величина θ может быть найдена из условия

Where

, F _eff = 1 / λ, θ = -η / λ. The value of F _eff can be called the filter efficiency, since it is related to the filter’s ability to suppress the components G _μk (for F _eff = 0, the values F _μ = θJ _μ do not depend on the set G _μk ). The value of θ can be found from the condition

The value of F _eff could also be found for a given value of F _trans from the last condition (813). However, it is easier to use filters with different values of F _eff and choose one that gives an acceptable result, and use the F _trans value obtained from the last equality (813) to quantify the relative fraction of the desired substance in the analyzed mixture.

As an optimal filter, one can take one that provides the maximum signal-to-noise ratio for the maximum square of the value after filtering, taking the average square of the values after filtering in the array as the noise level while moving away from the localization of the specified maximum square of the value greater than the specified distance. The criteria for the detection of the target compound are close to the expected localization of the maximum squared value after filtering and the achieved signal-to-noise ratio for it. Quantitative parameters of these criteria and estimates of the relative content of the target compound in the analyzed mixture are generated based on the analysis of calibration mixtures of known composition containing the corresponding target compounds. This concerns the average values of localizations and their dispersions for the maximum value of the square of the response of the digital filter to the data recorded and transformed as described above for calibration mixtures. Also determined are the levels of the ratio of the described signal-to-noise ratio corresponding to certain concentrations of the target compounds in the calibration mixtures and the corresponding calibration curves are constructed.

When analyzing ionic impurities in polar liquids, in particular, biomolecule ions in aqueous solutions, the following, illustrated in Fig. 2, methods for preliminary separation of the analyzed components. If at the bottom of the chamber (83) to create a conductive layer (86), isolated from the outer shell (82) of the chamber (83) by an insulator (90) and apply some fairly high voltage to it, for example, negative with respect to the shell (82), then an electric field (200) will arise between this shell and the layer (86). This field will shift positive ions (203) to the region of entry into the capillary (89), and negative (204) to the outer shell (82). Part of the positive ions will even enter the capillary (89) under the influence of a liquid flow (201). Further, however, they will not advance, since a field (202) of the opposite direction will act on them inside the capillary, because the potential of layer (86) is significantly lower than the potential in the region of the cloud of accumulated ions (206). The latter potential is positive and usually does not exceed 10 V. Only on average, neutral particles (208) will freely penetrate into the capillary (89) and then be discharged into the zone of formation of the analyzed ions (207) with a stream of liquid. For biomolecules, this will mean that only those are registered whose isoelectric point is close to the pH of the solution. The syringe (88) shown in Fig. 2, contains some buffer solution, which, under the influence of atmospheric pressure on the piston (213), flows into the chamber (83). As a result, the pH of the solution gradually changes, and new biomolecules with the corresponding isoelectric point will enter the capillary (89). Thus, the separation of biomolecules by their isoelectric points is achieved.

When the polarity of the voltage applied to the layer (86) changes, some of the ions (203), which were introduced by the fluid flow (201) into the capillary (89), begin to move along the capillary. In accordance with their mobility, these ions will alternately leave the capillary (89) in the form of more or less separated packets. Usually, in order to achieve the highest resolution of such mobility spectra, it is necessary to create electric fields of the greatest possible intensity, which leads to sufficiently short exit times for the peaks of such a spectrum. In this case, the natural limitation is the speed of the mass analyzer. For our time-of-flight mass spectrometer with orthogonal ion injection, the usual time of recording one mass spectrum with a range of m / z up to 1000 is 100 μs. An acceptable description of the shape of the peaks of the mobility spectrum requires about 10 mass spectra for each such peak. Those. the duration of such a peak should be about 1 ms, which imposes a limitation on the magnitude of the electric field strength (202). If there are no other restrictions, then this duration determines the maximum resolution of such mobility spectra. The expected exit time of all ions from the capillary (89), including ions with zero mobility, is determined by the rate of outflow of the solution from the capillary (89) and its length, which is about 1.5 cm in our system. At the outflow rate for atmospheric pressure in the chamber (83), about 2.5 cm / s, which corresponds to the above estimate of the volumetric flow rate of an aqueous solution of ~ 0.15 mm ³ / min from a capillary with a diameter of 10 μ at atmospheric pressure in the chamber (83), this time will be about 600 ms. This means, in this case, the maximum expected resolution will be around 600, which is a fairly high resolution in ion mobility.

It is clear that to obtain acceptable mobility spectra, their multiple accumulation is required, for example, for 600 s (10 min), so that 1000 mass spectra for each point of the mobility spectrum are accumulated. During this time, the conditions in the solution should not noticeably change. For this, it is enough, for example, to supply the analyzed solution rather than the buffer solution through the syringe (88), or to maintain a constant rate of the solution flowing out of the capillary (89) from the syringe (88) into the chamber (83) to supply some inert gas. Such accumulation can be realized by switching the polarity of the voltage across the layer with a period of 600 ms (89). In this case, the “single” mobility spectra of positive and negative ions will be recorded alternately, which must be separately accumulated, giving two final mobility spectra of positive and negative ions. The total accumulation time of these two mobility spectra under the described conditions will be 20 min.

Such spectra can be recorded for various pH values of the solution and / or concentrations, for example, sodium ions, by adding appropriate buffer solutions to the solution in the chamber (83). After establishing constant values of the pH sensors (214) and the concentration of sodium ions (215), the above procedure for obtaining mobility spectra is started. All this sequence of actions is repeated the desired number of times until a certain set of series of mass spectra is recorded for the selected ranges of pH values and / or concentrations of sodium ions in solution. In each series of mass spectra, we select those sets of mass spectra that can relate to biomolecules of interest, for example, those that correspond to their molecular masses, taking into account possible protonation or deprotonation, the inclusion of cations (sodium ions) and anions (ions chlorine, bromine, etc.). The choice of the type of cations and anions depends on the salt that was used in the preparation of the buffer solution. We summarize the mass spectra corresponding to the allowed peaks of the mobility spectra for the corresponding mass spectral peaks.

For each of these total mass spectra that make up the distribution of the numbers of charge carriers held in, we start the decomposition of such multidimensional charge distributions [33]. In accordance with the criterion formulated in [46], we find sites and corresponding mass spectra for each pair of pH values and concentrations of sodium ions, for which the found relative probabilities of proton and sodium ion retention are best described by equilibrium values for some ratio of the corresponding equilibrium constants. It seems that the totality of such relations, along with the isoelectric point of the corresponding biomolecule, can be taken as a characteristic of the structure of this biomolecule in solution and can be used to identify its isoforms in biological fluids. This assumption, of course, requires appropriate experimental studies and comparison with the data of other methods.

During the measurements described above, when sufficiently strong electric fields are created in the chamber (83) in the presence of open metal electrodes, electrolysis processes can occur that lead to etching of the material of these electrodes, to a change in the composition of the analyzed solution, and to the transformation of the analyzed components themselves. To prevent all of these processes, which may have undesirable consequences for the analyzes, it is possible to coat the said electrodes with a thin dielectric film. The technique of such a coating was developed previously with the participation of one of the authors of the present invention and was used to solve a variety of technological problems [47].

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Claims (21)

1. The method of structural-chemical analysis of impurity compounds in solutions or gases flowing into a vacuum through a capillary during the formation of ions detected by the mass analyzer under the influence of a supersonic gas stream containing ions and / or metastable excited particles, on the outgoing analyzed solution or gas, which differs the fact that the outflow of the analyzed solution or gas is made inside a linear radio-frequency trap, and the capillary at the output end is surrounded by a cylindrical shell with some gap rum from the capillary walls and an opening for entering the supersonic gas flow inside said gap. 2. The method according to p. 1, characterized in that the said buffer gas stream containing a mixture of inert gases is passed through an electron ionization source or a glow discharge zone under conditions ensuring the formation of ions and / or metastable excited atoms in this stream, at least , some of these inert gases. 3. The method according to p. 1, characterized in that they provide heating to a controlled temperature of the buffer gas at the inlet to the supersonic gas flow formation system having one or more cylindrical channels with a diameter comparable to the mean free path of gas atoms and a length sufficient for the formation of supersonic gas jets inside them. 4. The method according to p. 1, characterized in that they produce heating of the chamber containing the analyzed solution or gas to a predetermined temperature. 5. The method according to p. 1, characterized in that the transport of registered ions to the mass analyzer is carried out through the aforementioned radio-frequency linear trap, into which the input of the analyzed solution or gas is organized through the gap between the rods at the beginning of this trap with the exit of the analyzed solution or gas on some away from the axis of this trap. 6. The method according to p. 5, characterized in that the linear radio frequency trap is a radio frequency quadrupole. 7. The method according to p. 6, characterized in that the rods of the first half of the radio-frequency quadrupole are partitioned, and the electric power circuits for the first and second halves of the quadrupole are such that they allow the creation of a separately controlled quasilinear longitudinal constant field in the first half, independently generated by the constant voltage in the second half of the quadrupole and radio frequency quadrupole and oscillating fields for opposite pairs of rods for both halves of the quadrupole. 8. The method according to p. 7, characterized in that the input and output diaphragms of the quadrupole are multilayer with alternating conductive and dielectric layers, the outer layers of these diaphragms are conductive. 9. The method according to p. 8, characterized in that the conductive layer of the aforementioned input diaphragm on the side near the quadrupole is divided into sections to which antiphase radio frequency voltages with controlled frequency and amplitude are applied. 10. The method according to p. 9, characterized in that in the first half of the quadrupole creates a braking electric field for the ions of the buffer gas; the radio frequency voltage of the second half is increased compared with the first half so that it leads to the death of buffer gas ions and is acceptable for focusing large ions of m / z analyzed ions to the quadrupole axis; the voltage of the first section of the output diaphragm is increased compared to the voltage of the second half of the quadrupole, so as to achieve the optimal current of the analyzed ions. 11. The method according to p. 10, characterized in that in the first half of the quadrupole creates an oscillating voltage; the amplitude, direction and frequency of oscillations are chosen optimal for recording the desired flow of the selected analyzed ions. 12. The method according to p. 1, characterized in that the linear radio frequency trap is coaxially coupled to the mass analyzer, in particular, it can be a time-of-flight mass analyzer with orthogonal ion input. 13. The method according to p. 12, characterized in that for the implementation of coaxial pairing with the mass analyzer, a conical or wedge-shaped skimmer is used, the inlet or inlet of which at its apex is located on the axis of the linear radio-frequency trap. 14. The method according to claim 1, characterized in that an electric field is created in the analyzed solution in the direction of its outflow, accumulating solution ions of the corresponding sign in front of the output capillary; the electric field arising inside the capillary due to contact with the buffer gas ions accumulated in the quadrupole prevents the accumulation of the analyzed ions from the effluent solution, providing, on average, neutral particles from the solution exit into the formation zone of the detected ions. 15. The method according to p. 14, characterized in that the electrodes to which the voltage drop is applied to create the said electric field in front of the output capillary is coated with a thin dielectric film that impedes the electrolysis of the analyzed solution on these electrodes. 16. The method according to p. 14 or 15, characterized in that the polarity of the electric field in the analyzed solution in the direction of the outflow of this solution is reversed, ensuring the launch of the packet of solution ions accumulated at the inlet of the capillary into the capillary and their separation by mobility by an electric field inside the capillary . 17. The method according to p. 16, characterized in that the procedure described in p. 16 is periodically repeated with a certain time delay, providing sequential launch of neutral particles, accumulated positive ions, again neutral particles and then negative accumulated ions into the formation zone of the detected ions on average etc. with the possible accumulation of mass spectra of the corresponding ions. 18. The method according to p. 14 or 17, characterized in that the series of mass spectra are recorded sequentially in the selected range of mass to charge ratios with a gradual change in the composition of charge carriers in the solution in which the presence of the studied biomolecules is assumed or organized; a change in the composition of the charge carriers in the solution is ensured by replacing the part of the analyzed solution emerging through the capillary with a specially selected buffer solution; concentrations of small ions - charge carriers in the analyzed solution are determined by appropriate sensors; peaks corresponding to multiply charged ions of the studied biomolecule are detected in the mass spectra; decomposition of the resulting multidimensional charge distributions is performed for various concentrations of charge carriers in solution; from the totality of the determined probabilities of holding various charge carriers by separate ionogenic groups of the biomolecule, those that correspond to the equilibrium processes of substitution of charge carriers in solution and which give adequate estimates of the equilibrium constants of these processes are selected; the totality of such estimates is used to characterize the structure of the studied biomolecules in solution. 19. The method according to p. 2, characterized in that the analyzed gas mixture or solution is introduced into the chamber, in which constant controlled pressure and temperature are maintained; sequential registration of series of survey mass spectra is carried out with a stepwise change in the temperature of the chamber for the formation of the analyzed stream; by constructing and applying to the recorded series of mass spectra of selective digital filters built for known mass spectra of the target compounds, the presence and the concentration of the expected target compounds in the analyzed mixture are determined and evaluated. 20. The method according to p. 19, characterized in that for the exponentially decaying “tails” of the obtained ion current distributions with different m / z values, the best transition in the rms matrix from the previous set of values of the mentioned ion currents to the next such set is found; calculate the eigenvalues and eigenvectors of the found transition matrix; find an approximation of the said “tails” of distributions acceptable by the expected error by a linear combination of the minimum number of the mentioned eigenvectors with exponential decay factors determined by the corresponding eigenvalues; take the found set of such eigenvectors for the mass spectra of the detected components in the considered data set, and the calculated coefficients of the mentioned linear combination for approximate estimates of the relative contributions of these components to the analyzed mixture; these estimates can be refined by conducting appropriate calibration experiments. 21. The method according to p. 2, characterized in that the analyzed gas mixture or solution is exposed to a supersonic stream containing a mixture of inert gases and passed through an ion source of electron ionization at different energies of ionizing electrons, which provide significant changes in the composition of ions and metastable atoms in flow by comparing the recorded mass spectra at suitable electron energies with the corresponding mass spectra of the target compound, it is concluded that this compound is present or absent in the analyzed sample.

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