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НАУЧНОЕ ПРИБОРОСТРОЕНИЕ, 2018, том 28, № 4, c. 151-160 РАЗРАБОТКА ПРИБОРОВ И СИСТЕМ =
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THE INNOVATIVE DIRECTION OF THE DEVELOPMENT OF SCIENTIFIC INSTRUMENTATION — TIME-OF-FLIGHT
MASS SPECTROMETERS
© B. S. Slepak1, K. B. Slepak2
1 Institute for Analytical Instrumentation of RAS, Saint-Petersburg, Russia 2NRC "KurchatovInstitute" — CRISM "Prometey", Russia
The breakthrough scientific research in the field of development of analytical instrumentation, one of the areas of analytical instrumentation — time-of-flight mass spectrometry is being described. The creation of domestic time-offlight mass spectrometers implements the task of import substitution of foreign equipment, and refers to significant, risky for state organizations financing. The scientific instruments that do not have domestic analogues and illustrate the development of one of the most promising areas of scientific instrumentation are being presented. Time-of-flight mass spectrometry makes it possible to create the most powerful in terms of sensitivity, informativity and speed small-sized analytical systems with modern software for qualitative and accurate quantitative analysis of the composition and structure of chemical compounds.
Keywords: mass spectrometry, ion source, electrospray fluid, ion flow, space charge
A PROMISING DIRECTION IN THE DEVELOPMENT OF ANALYTICAL
INSTRUMENTATION IS THE CREATION OF INNOVATIVE INSTRUMENTS FOR IMPORT SUBSTITUTION
The Institute of Analytical Instrumentation of the Russian Academy of Sciences (IAI RAS) has for decades worked by conducting fundamental and applied scientific research and developed unique competences in the field of analytical instrumentation, and now produces prototypes of competitive instruments, organizing their small-scale or serial production.
One of the main tasks of analytical instrumentation IAI RAS sees in solving the problem of import substitution of instruments and equipment necessary for performing works on priority scientific directions, taking into account the needs of domestic and foreign markets, and also an annual increase in sales of devices [1, 2].
Mass spectrometry is practically the most powerful method of analyzing the composition, structure and quantities of chemical compounds in terms of sensitivity, informativeness and speed. The mass spectro-metry method is used in modern high-tech scientific fields, having the ability to analyze various substances: isotopes of chemical elements, complex biopolymers such as proteins and nucleic acids, distinguish microorganisms, detect compounds at nano-dimensional
levels, carry out qualitative and quantitative analysis of various mixtures consisting of thousands of organic compounds without their prior separation.
Instruments of the IAI RAS using the method of mass spectrometry have found their application: in chemistry, in physics, in biology, in medicine, in pharmaceutics, in ecology, in criminalistics, in antiterrorist activity, in control of the quality of food products, in nuclear research and other areas of scientific research [3-5].
The IAI RAS as well as foreign companies such as Agilent Technologies, Bruker Scientific Instruments, Thermo Fisher Scientific, LECO Corporation, Danaher Corporation, creates mass-spectrometric express diagnostics devices at the world level, solving the problem of diagnosing early stages of various diseases: oncology, cardiovascular, genetic.
In modern clinics, the instruments realizing molecular genetic methods and methods of ionization time-of-flight mass spectrometry, based on the use of physical innovative technologies, have replaced cultural diagnostics. World experience in the use of mass-spectrometric express diagnostics for the species identification of microorganisms extracted from clinical material confirms the high value of the method and the potential opportunity for direct indication of bacteria in the clinical material, which significantly shortens the time of analysis and opens up new resources for use in various sections of the microbiological diagnostics [6].
Modern mass spectrometry is based on the elemental base of a high level of integration, which allows to miniaturize equipment, using the latest technologies, contributing to the increase of the innovation level of the devices being created.
THE BENCHTOP TIME-OF-FLIGHT MASS SPECTROMETER МХ5310 (11)
The benchtop time-of-flight mass spectrometer MX5310(11) [7] is designed for solving a wide range of research and applied problems of medicine, biotechnology, pharmacology, environmental protection, criminology, and agricultural industry (Fig. 1).
The instrument operation principle is based on the method of producing ions from the solutions of substances under analysis.
Since instrument MX5310 (11) ensures highsensitive analysis of solutions of samples of various natures, it is possible: to diagnose diseases at early stages; to perform proteomic investigations; to control drug production and storage; to develop new drugs; to control food purity.
The instrument is produced in two modifications: MX5310 with the electrospray ion source (the liquid sample bulk velocity of up to 1 ml/min) and MX5311 with the nanoelectrospray ion source (the liquid sample bulk velocity of several nanoliters per minute). MX5310 (11) can be equipped with a liquid chromatograph.
ADVANTAGES
Advantages of the mass spectrometer MX5310 (11): analytical characteristics of instrument MX5310 (11) are comparable with the world-best ones in this instrument class; the instruments can work in both the "on-line" and "off-line" modes; the original software
Table 1. Basic performance characteristics of the mass spectrometer MX5310 (11)
Mass-spectrometric detection of the presence of the goal substance and impurities with the sensitivity no less than, M 10-15
Resolution at the peak half-height, minimum 7 000
Detectable mass number extreme range, up to, daltons 10 000
range, up to, daltons 20 000
Mass measurement accuracy, with internal calibration, % 10-15
Mass stability for 30 min, maximum, % 2 x 10-3
Overall dimensions, mm 1040 x 760 x 600
Fig. 1. The mass spectrometer MX5310 (11)
(TOF+) allows continuous monitoring of the analysis and high-speed data compression; since the instrument can work with domestic consumables, operating costs are; 15 times lower than in working with foreign analogues; in case of small-batch production, the instrument cost is considerably lower than that of foreign analogues of the same class.
BASIC PERFORMANCE CHARACTERISTICS
OF THE MASS SPECTROMETER МХ5310 (11)
The basic performance characteristics of the mass spectrometer MX-5310 (11) are presented at Table 1. Purity analysis of the insulin pharmaceutical form produced by different companies by using instrument MX5310 was performed. The comparison of insulin from different manufacturers (Fig. 2-4) for the presence of foreign impurities shows that the most pure is French insulin, and that Ukrainian insulin contains the greatest amount of impurities. The instrument is used for cancer diagnostics (Fig. 5).
Fig. 2. Control of the purity of insulin in the Ukrainian pharmaceutical industrial company
Hemulin
France
+4H '
tisa^m +SH 1
1 , I.L 1 J L
Fig. 3. Control of the purity of insulin in the French pharmaceutical manufacturing company
Fig. 4. Control of Russian pharmaceutical industrial company
Fig. 5. Diagnostics of cancer by using instrument MX5310
MASS SPECTROMETRIC COMPLEX MX5313
The domestic analytical complex MX5313 [8-14] is a highly sensitive world-class device (Fig. 6). The use of instrument complexes MX5313 allows to determine the composition of complex mixtures of various substances with high accuracy.
The analytical complex MX5313 allows to significantly reduce operating costs and speed up the maintenance of the device [15, 16].
Analytical complex MX5313 is designed for the quantitative analysis of complex (more than 50 components) mixtures of volatile and semi-volatile compounds. The analytical complex MX5313 allows for the quantitative analysis of most drugs, poisonous substances, explosives, pesticides, steroids and drugs.
The analytical complex consists of the following devices: a time-of-flight mass analyzer of the reflectron type with orthogonal injection of a continuous ion beam from a source that has an electron impact; a heated interface in the form of a gas chromatograph ("Crystal 5000") and a vacuum evacuation system based on the use of high-vacuum turbomolecular pumps [17-21].
The method of diagnostics of complex mixtures, using the Analytical Complex MX5313, allows to reliably detect hazardous substances for humans at enterprises that have harmful production. Dangerous to humans substances, as a rule, are not diagnosed by any other methods. The use of the MX5313 Analytical Complex in the course of environmental monitoring increases the reliability of the analysis results by accurately determining the mass of the analyte [22].
Fig. 6. Mass spectrometer complex MX5313
SOFTWARE FOR THE MX5313 ANALYTICAL COMPLEX
The software of the Analytical Complex MX5313 allows: control and management of the operation of the complex; registration of mass spectra; search by name and chemical formulas of substances stored in the National Institute of Standards and Technology (NIST) database; viewing structural formulas of substances stored in the NIST database; viewing the mass spectra of substances stored in the NIST database; search on demand in the NIST database of substances which mass spectra correspond to the registered mass spectrum by the Analytical Complex MX5313; determination of peaks on the graph of the total ion current "TotalIonCurrent" (TIC). The determination of the
peaks in the TIC graph allows: allocation of the peaks on the TIC spectrum; mapping of the peak mass center; scaling of TIC graph fragments; output of the peak parameters as a separate window.
MAIN TECHNICAL CHARACTERISTICS
OF THE MX5313 ANALYTIC COMPLEX
The basic performance characteristics of the mass spectrometer MX5313 are presented at Table 2. According to the recorded mass spectrum of the electron impact of PFTBA the results on the accuracy of determination of ion masses are given in Table 3. Re-
sults on the accuracy of determination of ion masses were determined at a voltage of 2100 V, 1000 scans at the detector.
The accuracy of the masses of the registered ions up to 5 ppm allows to improve the probability of recognition of the analytes.
Analytical characteristics of the MX5313 manufactured in the IAI RAS, at the level of the world's best samples in this class of devices. The device does not have any domestic analogues. The MX5313 analytical complex was developed by order of the Federal Medical and Biological Agency of Russia.
Table 2. Main technical characteristics
Resolution for mass 614 Yes, Perfluorotributylamine (PFTBA) 5000
Range of scanned masses, atomic mass unit (u) 30-1000
Scanning speed, spectra per second 200
Sensitivity, hexachlorobenzene at a signal-to-noise ratio 2 10-12, 30:1
Version of the analytical complex performance desktop
Power consumption, no more, kW 3
From AC power 220 V
Table 3. Results on the accuracy of determination of ion masses
N n / a Type Formula Neutral Theoretical Observed Error Yes Error ppm
1 PFTBA 69 CF3 68.9952096 68.994661 68.994661 0 0
2 PFTBA 69 C2F4 99.9936128 99.9930642 99.993074 0.0098 0.09800679
3 PFTBA 69 C2F4N 113.996687 113.996138 113.996069 0.069 0.60528366
4 PFTBA 69 C2F5 118.992016 118.991467 118.991974 0.507 4.26080972
5 PFTBA 69 C3F5 130.992016 130.991467 130.991944 0.477 3.64145856
6 PFTBA 69 C3F7 168.988822 168.988274 168.988923 0.649 3.84050315
7 PFTBA 69 C4F9 218.985629 218.98508 218.985257 0.177 0.80827424
8 PFTBA 69 C5F10N 263.987106 263.986557 263.986068 0.489 1.85236705
9 PFTBA 69 C8F16N 413.977525 413.976977 413.976126 0.851 2.05566987
10 PFTBA 69 C9F18N 463.974332 463.973783 463.974128 0.345 0.74357649
11 PFTBA 69 C9F20N 501.971138 501.970589 501.970589 0 —
possible to obtain quasimolecular ions of thermolabile compounds directly from the solution. Ions are transported from the ionization region at atmospheric pressure through the differential pumping system to the high-vacuum region of the mass analyzer. As a mass analyzer, a time-of-flight analyzer with orthogonal ion input is used. When the instrument is operated in combination with a liquid chromatograph, a mass chromatogram is obtained by summing the total intensity of the ion current in each mass spectrum. The amount of substance required for such an analysis and introduced into the column of the chromatograph is 1 pg [30-35].
THE MAIN TECHNICAL CHARACTERISTICS OF THE ANALYTICAL COMPLEX MX5313
The main technical characteristics of the analytical complex MX5313 are presented in Table 4.
Fig. 7. Time-of-flight mass spectrometer with electrospray MX5303
Table 4. The main technical characteristics of the Analytical Complex MX5313
Resolution of the mass spectrometer at 50% of the peak height of the mass spectrum 10 000
The range of recorded mass numbers of the mass spectrometer (taking into account multiply charged ions), Yes Up to 10 000
Accuracy of mass determination (with internal calibration), % 10-4
The speed of full spectrum recording, spectra per second, not less than 10
The detection limit for gramicidin C at a flow of 1 ^l / min, M 10-15
TIME-OF-FLIGHT MASS SPECTROMETER WITH ELECTROSPRAY MX5303
The mass spectrometer is designed for the analysis of thermally unstable substances of organic and bio-organic origin directly from solutions.
The device can work in conjunction with a liquid chromatograph.
The new generation MX5303 mass spectrometric complex (Fig.7) is based on the method of obtaining ions from solutions of bioorganic compounds. The MX-5303 mass spectrometer with electrospray can be used to solve a wide range of biochemical problems [23-29].
Examples of such problems solved with the help of mass spectrometry with "soft" ionization methods areas follows: research of cellular and molecular bases of carcinogenesis, analysis of protein-protein interactions in DNA repair complexes, search for disease markers (cell pathology, study of protein composition).
The device uses electrospray ionization of the analyzed solution at atmospheric pressure, which makes it
APPLICATION OF MX5303 IN COMBINATION WITH A LIQUID CHROMATOGRAPH FOR THE ANALYSIS OF INSULIN SYNTHESIS PRODUCTS
Mass spectrometer MX5303, manufactured by IAI RAS, has high analytical characteristics of similar world-class devices (Fig. 8, 9). The MX5303 mass spectrometer operates both on-line and off-line. Mass spectrometer MX5303 is equipped with original software TOF-Plus, which allows continuous monitoring of the analysis procedure and high-speed compression of data without information loss. The MX5303 mass spectrometer has no domestic counterparts.
Fig. 8. Analysis of hydrolyzate products of the hybrid protein "off-line"
TOP* fHAttfl MtM|
1«» № 140» ÏW*
* j*p m m «F *m m fui i'IKi * m w>
m » «H M Ulli1 ab» '™j™ JLTI
11» JX 1«
Fig. 9. Analysis (HPLC-MS) of the tryptichydrolyzate of the hybrid protein
TIME-OF-FLIGHT MASS SPECTROMETERS MX5310 (11), MX5303 AND
MASS-SPECTROMETRIC COMPLEX MX5313,
PRODUCED BY IAI RAS, ON THE MARKET OF SCIENTIFIC INSTRUMENT MAKING
Time-of-flight mass spectrometers MX5310 (11); MX5303 and MX5313 mass spectrometry serially produced by IAI RAS successfully compete in the domestic and foreign markets for scientific instrumentation with the following foreign companies: Thermo Fisher Scientific; LECO Corporation; Waters Corporation; JEOL USA, Inc. (Table 5).
Time-of-flight mass spectrometers MX5310 (11); MX5303 and MX5313 mass spectrometry have been used in research organizations, institutions of higher professional education and institutions of the Russian Academy of Sciences. Time-of-flight mass spectrometers MX5310 (11); MX5303 and MX5313 mass spectrometry are operated by organizations working, in particular, in the field of creating new methods for diagnostics of diseases at an early stage — oncology, cardiovascular diseases, genetic diseases; in the field of creation, control of medicinal preparations, both in the production process and in the composition of finished medicines for compliance with their certificate; in the field of criminalistics — the trace analysis of drugs in biological fluids. Mass spectrometric complexes MX5313 can be used in the following areas: analytical chemistry, chemical synthesis, toxicology, forensic and clinical analysis of toxic preparations, analysis of pesticides in food and drinking water quality control, analysis of dioxins and nitrofurans, metabolism of drugs, control of psychotropic drugs, analysis of explosives, analysis of oil and oil products [36].
Domestic time-of-flight mass spectrometers implement a method for processing mass spectra of pep-tides to extract information on the masses of sample molecules based on analysis and decomposition of the structure of the mass spectrum using statistical data on the form of isotope distributions of molecular ions of peptides, as well as a method for controlling the production of genetically engineered insulin of ahuman with the help of tandem of HPLC-MS in the direct injection mode of the sample [37, 38].
SIMION 7.0 software with original modules developed in the IAI RAS was used for development of time-of-flight mass spectrometers manufactured by IAI RAS and for optimizing its ion-optical parameters.
IAI RAS developed a theory and carried out experimental studies of a planar multi-reflective time-of-flight mass analyzer, a theory of time-of-flight mass analyzers of a new type that allows to realize a fundamentally new tandem mass spectrometric (MS-MS) analysis in the "nested time" mode has been created.
Table 5. Comparison of analytical characteristics of mass spectrometric analyzers
Characteristics Mass Spectrometers
Pegasus TruTOF AccuTOF GC GCT H-TOF AutoSpec DSF
Manufacturer LECO LECO JEOL Waters Thermo Waters Thermo
Analyzer type Time-offlight (TOF) Time-offlight (TOF) Time-offlight (TOF) Time-offlight (TOF) Quadrupole (Q) Magnetic sector (EBE) Magnetic sector (EBE)
Resolution 1000 2000 5000 7000 1000 80 000 60 000
Detection limit 1 nr HCB 2 nr HCB 2 nr OFN 3 nr OFN 1 nr OFN 100 <J)r OFN 100 (J)r OFN
(s/n > 10) (s/n > 10) (s/n > 100) (s/n > 50) (s/n > 400) (s/n > 400) (s/n > 300)
Recordings peed of spectra 500 cps / sec 80 cps / sec 25 cps / sec 10 cps / sec 1-10 cps / sec 0.1-1 cps / sec 0.1-1 cps / sec
Arrangement Floor Desktop Floor Desktop Desktop Floor Floor
The IAI RAS implements the creation of time-offlight mass spectrometers that perform the function of import substitution in the market of scientific instrument making.
The Ministry of Science and Higher Education of Russia, defending the interests of the subordinate institutions of science, implements one of the types of state economic policy to replace imports with domestic products during the period of anti-Russian sanctions, thereby protecting the domestic producer by replacing imported scientific instruments and technologies with scientific instruments of national production.
A positive scenario for the development of domestic instrumentation provides for financing by the Ministry of Science and Higher Education of Russia of fundamental scientific research on promising areas of scientific instrumentation in order to increase the competitiveness of domestic products through the development of high-tech, science-intensive products with relatively high added value.
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Contacts: Slepak Boris Semyenovich, slepak@mail.ru
Article received in edition 17.08.2018
НАУЧНОЕ ПРИБОРОСТРОЕНИЕ, 2018, том 28, № 4, c. 151-160 РАЗРАБОТКА ПРИБОРОВ И СИСТЕМ =
УДК 338.001.36 + 338.012; 543.51; 577.112.5 + 621.384.8
1 2 © Б. С. Слепак , К. Б. Слепак
ИННОВАЦИОННОЕ НАПРАВЛЕНИЕ РАЗВИТИЯ НАУЧНОГО ПРИБОРОСТРОЕНИЯ — ВРЕМЯПРОЛЕТНЫЕ МАСС-СПЕКТРОМЕТРЫ
1 Институт аналитического приборостроения РАН, г. Санкт-Петербург 2НИЦ "Курчатовский институт " — ЦНИИ КМ "Прометей "
Описаны прорывные научные исследования в области развития аналитического приборостроения, одного из направлений аналитического приборостроения — времяпролетной масс-спектрометрии. Создание отечественных времяпролетных масс-спектрометров реализует задачу импортозамеще-ния зарубежного оборудования, и относится к значительному, рискованному для государственных организаций финансированию. Представлены не имеющие отечественных аналогов научные приборы, которые иллюстрируют развитие одного из наиболее перспективных направлений научного приборостроения. Времяпролетная масс-спектрометрия позволяет создавать самые мощные по чувствительности, информативности и быстроте малогабаритные аналитические системы с современным программным обеспечением для качественного и точного количественного анализа состава и структуры химических соединений.
Кл. сл.: масс-спектрометрия, источник ионов, электрораспыление жидкости, ионный поток, объемный заряд
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Контакты: Слепак Борис Семенович slepak@mail.ru
Материал поступил в редакцию: 17.08.2018
