Ion Source Of Mass Spectrometer Research Articles

Investigation of liquid chromatography-mass spectrometry analysis of a peptide aldehyde SJA6017 with identifying its hemiacetal, gem-diol, and enol ether.

The quantitative analysis of SJA6017, a peptide aldehyde inhibitor of calpain (Calpain Inhibitor VI), has encountered challenges in preclinical drug studies. The complex reverse-phase HPLC chromatographic behavior exhibits two peaks, each containing multiple species. An liquid chromatography-mass spectrometry (LC-MS/MS) study proposed an explanation for this phenomenon, caused by the amide aldehyde structure of SJA6017. Four chemical species corresponding to the two HPLC peaks have been identified as SJA6017 and its methyl hemiacetal, methyl enol ether, and gem-diol. In many instances of preclinical studies, methanol is favored as a substitute for DMSO. The hemiacetal is formed when the amide-activated peptide aldehyde reacts with methanol, which can then be further dehydrated in the mass spectrometer ion source under high temperature to form the methyl enol ether. The hemiacetal and gem-diol can also be decomposed to SJA6017 in the ion source. Additionally, the amide-activated peptide aldehyde can easily hydrate to the gem-diol of SJA6017 during sample incubation or sample preparation. The hemiacetal and gem-diol of SJA6017 are stable enough to have different retention times in the liquid chromatography, which explains why SJA6017 appears as two peaks, each containing multiple species. An LC-MS/MS tandem quadrupole mass spectrometer quantitative analysis method is proposed, enabling the analysis of these types of samples. This work serves as both an illustrative example and a cautionary note for mass analysis, sample incubations, and sample preparations involving compounds of peptide aldehyde, including similar aldehyde-containing metabolites, especially when methanol is present. This study provides the information needed to understand peptide aldehyde behavior at various steps of preclinical in vitro studies in the presence of methanol. It has assisted in the development of the SJA6017 bioanalysis method and will also aid in the development of bioanalysis methods for similar peptide aldehydes.

From droplets to ions: a comprehensive and consecutive ion formation modelling in atmosphere pressure interface of electrospray ionization mass spectrometry.

In this study, we propose a novel ion formation simulation method for electrospray ionization (ESI) and atmosphere pressure interface (API). In this method, not the sheer particle trajectory, but the evolution of droplets and the offspring of gaseous ions are introduced instead. For the first time, the dynamic droplet-to-ion transformation process in the API of ESI-MS is visualized. The results suggest that this model provides a better understanding of the ion evolution mechanism and we propose a way for mass spectrometer structure optimization and ion source parameter adjustment in new aspects.

Teaching a New Dog Old Tricks: Ultrafast Liquid Chromatography/Tandem-Mass Spectrometry Analysis of Nine ß-Lactam Antibiotics for Improved Therapeutic Drug Monitoring.

Therapeutic drug monitoring (TDM) of β-lactam antibiotics provides critical knowledge in hospital intensive care unit environments to support dosing within the narrow window between therapeutic failure and toxicity. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is the most suitable analytical technique for these drugs; however, clinicians, patients, and laboratories would benefit from shortening the timeframe between the collection of samples and reporting of results. The authors developed a very rapid LC-MS/MS method for 9 β-lactam antimicrobial drugs on a commercial core-shell reverse-phase LC column by exploiting the performance of such stationary phase materials at a high mobile-phase linear velocity and using a simple flow split to optimize ionization conditions in the mass spectrometer ion source. The method's performance was assessed using a currently validated routine LC-MS/MS assay performed on the same instrument. Routine ß-lactam assays were reduced from >6 minutes per sample to less than 2 minutes with improved chromatographic resolution, while still maintaining acceptable analytical performance (average correlation coefficient: 0.99670, interday imprecision: 2.0%-10.8%, and bias: -1.68%), hence generating results in agreement with an existing validated method for patient and quality assurance program samples. Time-critical results, such as those for β-lactam antimicrobials, may be reported by the TDM laboratory several hours earlier than current methods allow, providing improved patient care and generating capacity on LC-MS/MS instruments for larger batch sizes and/or additional assays. The simple-to-implement technique demonstrated in this study may be applicable to other TDM assays or any LC-MS/MS method where faster turnaround times are desirable.

A versatile vacuum ultraviolet ion source for reduced pressure bipolar chemical ionization mass spectrometry

Abstract. We present the development of a chemical ionization mass spectrometer ion source specifically designed for in situ measurements of trace gases in the upper troposphere and lower stratosphere. The ion source utilizes a commercially available photoionization krypton lamp, primarily emitting photons in the vacuum ultraviolet (VUV) region at wavelengths of 124 and 117 nm (corresponding to energies of 10 and 10.6 eV, respectively), coupled to a commercially available Vocus proton transfer reaction mass spectrometer. The VUV ion source can produce both negative and positive reagent ions; however, here we primarily focus on generating iodide anions (I−). The instrument's drift tube (also known as ion–molecule reactor) operates at pressures between 2 and 10 mbar, which facilitates ambient sampling at atmospheric pressures as low as 50 mbar. The low operating pressure reduces secondary ion chemistry that can occur in iodide chemical ionization mass spectrometry (CIMS). It also allows the addition of water vapor to the drift tube to exceed typical ambient humidity by more than 1 order of magnitude, significantly reducing ambient humidity dependence of sensitivities. An additional benefit of this ion source and drift tube is a 10- to 100-fold reduction in nitrogen consumed during operation relative to standard I− ion sources, resulting in significantly reduced instrument weight and operational costs. In iodide mode, sensitivities of 76 cps ppt−1 for nitric acid, 35 cps ppt−1 for Br2 and 8.9 cps ppt−1 for Cl2 were achieved. Lastly, we demonstrate that this ion source can generate benzene (C6H6+) and ammonium (NH4+) reagent ions to expand the number of detected atmospheric trace gases.

An improved analytical method for quantitation of nitrosamine impurities in ophthalmic solutions using liquid chromatography with tandem mass spectrometry

Nitrosamines are known to be a group of probable human carcinogens that are generally formed by the reaction of secondary and tertiary amines, amides, carbamates, or derivatives of urea with nitrite or other nitrogenous agents. Nitrites are common nitrosating impurities that have been reported in many excipients at part per million levels. Guidelines from FDA and EMA have identified potential nitrosamine impurities that could theoretically be present in drug products. As part of the guidelines, it's crucial to have an established method to screen drug substances and products. Furthermore, drug products containing buffers/salts and polymeric excipients were challenging to test as current literature methods would not retain early-eluting nitrosamine impurities long enough to bypass the salts/excipients from the mass spectrometer ion source using a converter switch.An improved analytical method, aligned with the FDA and EMA guidance, using HPLC/MS/MS, was developed by our lab to address the above unmet need. The method demonstrates an excellent sensitivity and linearity range (0.2–200 ng/mL). It was also shown that the method tolerates much higher organic solvents percentage as diluent. Interested readers can use the method as a starting point for further optimization for analyzing their specific drug substances and drug products.

Ion-Molecular Derivatization Reactions of Alcohols in a “Direct Analysis in Real Time” (DART) Mass Spectrometer: 4-N,N-Dimethylaminopyridine as a New Efficient Reagent

Gas-phase on-line derivatization in the ion source of a DART mass spectrometer is a new approach to the efficient detection of alcohols in complex matrices. It does not require any special sample handling; it is based just on mixing an alcohol with a nitrogen-containing compound with high proton affinity. The resulting N-alkyl-derivatized cations appear in DART spectra as very characteristic and highly intense signals. In addition to the earlier used pyridine and quinoline, we propose a new reagent, 4-N,N-dimethylaminopyridine (4-DMAP), having a higher proton affinity. It is shown that DART mass spectra recorded for alcohols in the presence of an equimolar mixture of pyridine and 4-DMAP reveal peaks that are mainly due to the 4-DMAP quaternization cation. This indicates a highly competitive ability of this reagent to get protonated and then predominantly participate in ion-molecular reactions with alcohols under study. It is suggested that 4-DMAP provides high sensitivity in the analysis of aliphatic and alicyclic primary and secondary alcohols.

High-performance liquid chromatography-tandem mass spectrometry with post-column pH modification: Independent pH optimization for chromatographic separation and electrospray ionization.

In recent environmental research, multi-methods using high-performance liquid chromatography-mass spectrometry (HPLC/MS/MS) have become more and more important for the analysis of organic micropollutants in environmental matrices. As the targeted compounds usually have different physicochemical properties, the optimization of these methods is challenging. The pH in the electrospray of the mass spectrometer ion source was modified independently of the one used for the HPLC separation, using a post-column HPLC flow to make the spray acidic or alkaline. The method development was carried out manually in a systematic multistep way. The method used for the analysis of organic biocides (e.g., terbutryn, propiconazole, and isothiazolinones) was optimized. It was shown that the use of a neutral as well as an acidified gradient could not be optimized for all target compounds, whereas a neutral gradient with post-column acidification was optimum for all target compounds. Acidic or alkaline post-column infusion allows pH optimization for ionization conditions, independent of the pH optimization for chromatographic separation. The introduction of an additional modifier might also allow the minimization of matrix effects or directed formation of sodium adducts, without affecting the chromatographic separation.

Behavior of transition metal salts during the electrospray ionization process

A study of the behavior of transition metal salts during the electrospray ionization (ESI) process using a quadrupole ion trap mass spectrometer and novel ion source is reported. The unique results in both positive and negative modes for multiple salts of 28 different cations are discussed. In positive mode, the metal cations formed clusters with the solvents, following the pattern [M + (solvent)n]+, with maximum observed values for n of 5. In general, transition metals with more than one oxidation state, such as iron, cobalt, and chromium, produced more complicated mass spectra, because the ions formed also included multiples of the anion. In negative mode, the cations formed clusters with the anions of the salts, following the pattern [My + Xn]-. The relationship between y and n correlates to the oxidation state of the cation, with maximum observed values for y and n of 3 and 7, respectively. For some environmental applications, studies in negative mode demonstrate an alternative to specialized elemental analysis instrumentation such as ICP/MS or AMS, as well as complicated sample preparation, such as the use of chelating complexes. This is especially applicable for the analyses of mercury and lead, as these species form only a few, predictable ions. For instance, mercury present in seawater forms a single ion, [Hg + Cl3]-, which can be readily isolated from the sodium chloride clusters in the background with a non-specialized ion trap mass spectrometer using ESI, and can be verified by its characteristic isotopic pattern.

Evaluation of selected buffers for simultaneous determination of ionic and acidic pesticides including glyphosate using anion exchange chromatography with mass spectrometric detection

Ion chromatography coupled with mass spectrometry is an established technique for determination of ionic analytes, however, sophisticated buffer removal equipment is required to eliminate inorganic compounds from the eluate before introduction into the ion source of mass spectrometer. A standard high-performance liquid chromatography coupled with tandem mass spectrometry setup using an ion exchange column (Metrosep® A Supp 5) is proposed as an alternative approach. For that reason, some buffers including non-volatile carboxylic acid based solutions have been evaluated for simultaneous trace determination of ionic and acidic pesticides including glyphosate in the same extract without a need for sophisticated buffer removal equipment. Two differently designed ionisation sources were compared qualitatively for the application of non-volatile buffers. The study revealed that the choice of buffers had a strong influence on matrix effects in case of spiked extract injections. Finally, pesticides with very different physicochemical properties (logP<0, logP≥0) and structures (containing carboxylate, phosphonate, azolide, azanide, phenolate, bromate, and chlorate moieties) were quantified in spiked beer and oat extracts with acceptable recoveries (80-110%) using tandem mass spectrometry detection with AB SCIEX QTRAP 5500 instrument after separation using edetate buffer.

Ion-Optical System of an Ion Source with Energy Focusing in the Formed Beam

Ways to reduce ion beam intensity losses in a mass spectrometric ion source, which are caused by chromatic aberration of its immersion ion-optical system, are considered. These losses are rather significant in forming a beam from ions with a large energy spread. The reduction of aberration losses is especially important when ion sources are used jointly with mass analyzers with energy focusing. It is shown that these losses can be reduced significantly by using a new type of ion-optical system of the ion source, which includes achromatic elements. A special method for calculating such elements is given. Computer simulations have shown high efficiency of such elements in the ion-optical path of ion sources of mass spectrometers.

Ионно-оптическая система источника ионов с фокусировкой по энергии в формируемом пучке

AbstractWays to reduce ion beam intensity losses in a mass spectrometric ion source, which are caused by chromatic aberration of its immersion ion-optical system, are considered. These losses are rather significant in forming a beam from ions with a large energy spread. The reduction of aberration losses is especially important when ion sources are used jointly with mass analyzers with energy focusing. It is shown that these losses can be reduced significantly by using a new type of ion-optical system of the ion source, which includes achromatic elements. A special method for calculating such elements is given. Computer simulations have shown high efficiency of such elements in the ion-optical path of ion sources of mass spectrometers.

Towards the limits: Analysis of microscale 14C samples using EA-AMS

The coupling of an elemental analyzer (EA) to the gas ion source of an accelerator mass spectrometer (AMS) allows to perform online radiocarbon (14C) analysis of small combustible samples. EA-AMS measurements of small and ultra-small samples containing carbon in the range of 5–100 µg are performed on a routine basis at the MICADAS at ETH Zurich. Samples are encapsulated into vessels prior to combustion in the EA, which introduces extraneous C. The mass and fraction modern (F14C, i.e. the activity ratio of the sample relative to a modern reference material) of this constant contamination was characterized for various vessel materials and shapes. Different vessel cleaning procedures and storage effects were investigated. A minimum contamination mass of 0.10 ± 0.02 µg C per vessel was found for baked Al boats stored in GC-vials. Analysis of standard materials was then performed in order to assess contamination mass and fraction modern of the coupled setup. By applying the model of constant contamination, a mass of 0.44 ± 0.13 µg C and a F14C of 0.48 ± 0.14 were derived. Based on these findings, the mass-dependent detection limit (MDL) was calculated indicating that for a sample containing 5 µg C the F14C has to be superior to 0.03 to make it distinguishable from the background level. Finally, ultra-small samples of three certified reference materials (IAEA C5, C6, C7) were analyzed and corrected according to the model of constant contamination. For all three materials the corrected data was in agreement with the nominal values within the uncertainties.

Features of tests of miniature gas-filled spark gaps on tightness in the conditions of unstable work ion source of mass spectrometer

Features of tests of miniature gas-filled spark gaps on tightness in the conditions of unstable work ion source of mass spectrometer

Degradation of the Neonicotinoid Pesticides in the Atmospheric Pressure Ionization Source.

During the analysis of neonicotinoid pesticide standards (thiamethoxam, clothianidin, imidacloprid, acetamiprid, and thiacloprid) by mass spectrometry, the degradation of these pesticides (M-C=N-R is degraded into M-C=O, M is the skeleton moiety, and R is NO2 or CN) was observed in the atmospheric pressure ionization interfaces (ESI and APCI). In APCI, the degradation of all the five neonicotinoid pesticides studied took place, and the primary mechanism was in-source ion/molecule reaction, in which a molecule of water (confirmed by use of H218O) attacked the carbon of the imine group accompanying with loss of NH2R (R=NO2, CN). For the nitroguanidine neonicotinoid pesticides (R=NO2, including thiamethoxam, clothianidin, and imidacloprid), higher auxiliary gas heater temperature also contributed to their degradation in APCI due to in-source pyrolysis. The degradation of the five neonicotinoid pesticides studied in ESI was not significant. In ESI, only the nitroguanidine neonicotinoid pesticides could generate the degradation products through in-source fragmentation mechanism. The degradation of cyanoamidine neonicotinoid pesticides (R=CN, including acetamiprid and thiacloprid) in ESI was not observed. The degradation of neonicotinoid pesticides in the ion source of mass spectrometer renders some adverse consequences, such as difficulty interpreting the full-scan mass spectrum, reducing the sensitivity and accuracy of quantitative analysis, and misleading whether these pesticides have degraded in the real samples. Therefore, a clear understanding of these unusual degradation reactions should facilitate the analysis of neonicotinoid pesticides by atmospheric pressure ionization mass spectrometry. Graphical Abstract.

Performance evaluation of a miniature magnetic sector mass spectrometer onboard a satellite in space.

With the rapid development of space technology in China, it is urgent to use mass spectrometer to detect the space environment. In this work, a space miniature magnetic sector mass spectrometer is evaluated, which consists of three subsystems: (1) physical unit, (2) electric control unit, (3) and high voltage power. It has 90° magnetic sector-field analyzer with double trajectory, in which a trajectory measurement range is from 1 to 12 amu, the other range is from 6 to 90 amu.The mass spectrometer has two work models, one is used to measure space neutral gas when the filament of mass spectrometer ion source turned on, the other is used to measure space charged ions when the filament turned off. The absolute resolution of this device is less than 1 amu, the minimum detectable ion current is about 10-13 A, and the sensitivity is 10-6 A/Pa (N2). Its overall size is 170 mm × 165 mm × 170 mm, its weight is 4.5 kg, and its power consumption is 18 W. A series of environmental adaptability tests, including high and low temperature cycle, shock, vibration, thermal vacuum cycle, were carried out on the ground before launching, and sensitivity and peak position were also calibrated on the ground. In November 2012, the mass spectrometer was carried by an experimental satellite to 499 km sun synchronization and is still working right now. It successfully detected the atmosphere compositions both in the satellite orbit and gas-emitted from satellite, including O, He, 12CO2, 13CO2, H2, N2, O2, H2O, and so on.

An improved ion source for thermal ionization mass spectrometer

The ion source of a thermal ionization mass spectrometer (TIMS) has been designed to enhance the source sensitivity by modifying the geometry of extraction lens. Computer simulation studies on different combinations of the electro-static lens components and experimental validations were carried out. This also involved designing a robust triple filament assembly in a home-built TIMS. A good agreement between the simulated and experimental results, led to overall improvements in terms of the consistency of the source performance, a higher through put and an overall sensitivity enhancement by a factor of two.

A Continuous-Flow Gas Interface of a Thermal/Optical Analyzer With14C AMS for Source Apportionment of Atmospheric Aerosols

AbstractThis article reports on the performance of a continuous-flow interface for CO2gas feeding into the ion source of a 200-kV accelerator mass spectrometer (AMS) in splitless mode. Distinct CO2fractions and subfractions produced by a commercial Sunset OC/EC (organic carbon/elemental carbon) analyzer from ambient atmospheric aerosols filters are injected into the source and then analyzed by their14C/12C ratio in real time. New features are revealed from organic aerosol subfractions, which thermally desorb close to each other and are only visible by real-time analysis. An optimized setup for this purpose is presented for the measurement of CO2amounts from 3 to 45 μg C. Efficiencies of 4.5–8.0% for the formation of C-ions from CO2are obtained for sample masses of 5–10 μg C and carbon mass flow rates below 2 µg min–1. However, this ionization efficiency is substantially suppressed at high carbon mass flow rates. The potential of this method for a refined apportionment of aerosol sources is demonstrated with ambient filter samples.

Determination of Dihydrobenzoacridinone Structures by NMR, IR, and UV Spectroscopy and Mass Spectrometry

Introduction. Synthetic benzoacridinone derivatives are critical because of their applications as luminescent materials [1], antitumor drugs [2], and antibiotics [3]. The activity of such compounds was found to depend on the location of the carbonyl in the cyclic system [4]. Therefore, the location of the carbonyl in the fi nal product from three-component condensation of 2-naphthylamine, aromatic aldehydes, and dimedone is important because 9,9-dimethylor 10,10-dimethyl dihydrobenzoacridinones can be produced. The goal of the present work was to elucidate the structures of synthesized dihydrobenzoacridinone derivatives IVa–IVf. Experimental. 2-Naphthylamine (I, 1.43g, 0.01 mol), the appropriate aromatic aldehyde (IIa–IIf, 0.01 mol), and dimedone (III, 1.4 g, 0.01 mol) were refl uxed in EtOH until crystals of IVa–IVf began to precipitate (30–60 min) and then cooled. The resulting precipitate was fi ltered off, rinsed with Et2O, and recrystallized from EtOH:C6H6 (1:1). PMR and 13C NMR spectra were recorded from DMSO-d6 solutions (2–5%) on an Avance-500 spectrometer (BrukerBiospin, operating frequency 500.13 and 125.77 MHz for 1H and 13C). Chemical shifts were determined relative to TMS internal standard. COSY-45, NOESY, HSQC, and HMBC two-dimensional correlation spectra of IVa, IVd, and IVe were recorded in order to confi rm the structures and refi ne the resonances. All experimental results were obtained and processed using Topspin 2.1 software. IR spectra were recorded from thin layers or KBr pellets on a Protege-460 FTIR spectrophotometer (Nicolet). UV spectra of EtOH solutions (1·10–4 M) were taken on a Cary-300 spectrophotometer (Varian). Mass spectra of the synthesized compounds were measured using an Agilent 6890N gas chromatograph with an Agilent 5975 Inert mass-selective detector operating in electron-impact mode (70 eV) and was tuned to maximum sensitivity for the determined compounds. An HP-5ms capillary column (30 m × 0.25 mm × 0.25 μm) was connected directly to the mass spectrometer ion source. Samples were injected as CH2Cl2 solutions. Results and Discussion. Structures of synthesized 9,9-dimethyl-12-[5-(4-nitrophenyl)furan-2-yl]-9,10-dihydrobenzo[a] acridin-11-(7H,8H,12H)-one (IVa), 9,9-dimethyl-12-[5-(4-methoxy-2-nitrophenyl)furan-2-yl]-9,10-dihydrobenzo[a]acridin11-(7H,8H,12H)-one (IVb), 9,9-dimethyl-12-[5-(4-nitrophenyl)thiophen-2-yl]-9,10-dihydrobenzo[a]acridin-11-(7H,8H,12H)one (IVc), 9,9-dimethyl-12-[5-(3-nitrophenyl)thiophen-2-yl]-9,10-dihydrobenzo[a]acridin-11-(7H,8H,12H)-one (IVd), 12-[5-(4-bromophenyl)-1-methyl-1H-pyrrol-2-yl]-9,9-dimethyl-9,10-dihydrobenzo[a]acridin-11-(7H,8H,12H)-one (IVe), and 12-[5-(2-bromophenyl)-1-methyl-1H-pyrrol-2-yl]-9,9-dimethyl-9,10-dihydrobenzo[a]acridin-11-(7H,8H,12H)-one (IVf) were elucidated using UV, IR, PMR, and 13C NMR spectroscopy and mass spectrometry. The results indicated that condensation of 2-naphthylamine (I), aromatic aldehydes IIa–IIf, and dimedone (III) produced 9,9-dimethyl-12-[5-(aryl)furan-(or thiophen,

Ion mobility spectrometry-mass spectrometry examination of the structures, stabilities, and extents of hydration of dimethylamine-sulfuric acid clusters.

We applied an atmospheric pressure differential mobility analyzer (DMA) coupled to a time-of-flight mass spectrometer to examine the stability, mass-mobility relationship, and extent of hydration of dimethylamine-sulfuric acid cluster ions, which are of relevance to nucleation in ambient air. Cluster ions were generated by electrospray ionization and were of the form: [H((CH3)2NH)x(H2SO4)y](+) and [(HSO4)((CH3)2NH)x(H2SO4)y](-), where 4 ≤ x ≤ 8, and 5 ≤ y ≤ 12. Under dry conditions, we find that positively charged cluster ions dissociated via loss of both multiple dimethylamine and sulfuric acid molecules after mobility analysis but prior to mass analysis, and few parent ions were detected in the mass spectrometer. Dissociation also occurred for negative ions, but to a lesser extent than for positive ions for the same mass spectrometer inlet conditions. Under humidified conditions (relative humidities up to 30% in the DMA), positively charged cluster ion dissociation in the mass spectrometer inlet was mitigated and occurred primarily by H2SO4 loss from ions containing excess acid molecules. DMA measurements were used to infer collision cross sections (CCSs) for all identifiable cluster ions. Stokes-Millikan equation and diffuse/inelastic gas molecule scattering predicted CCSs overestimate measured CCSs by more than 15%, while elastic-specular collision model predictions are in good agreement with measurements. Finally, cluster ion hydration was examined by monitoring changes in CCSs with increasing relative humidity. All examined cluster ions showed a modest amount of water molecule adsorption, with percentage increases in CCS smaller than 10%. The extent of hydration correlates directly with cluster ion acidity for positive ions.

Coupled Space- and Velocity-Focusing in Time-of-Flight Mass Spectrometry-a Comprehensive Theoretical Investigation.

A comprehensive theoretical calculation that couples space- and velocity-focusing is developed for optimizing the design of a time-of-flight (TOF) mass spectrometer. Conventional designs for ion sources of TOF mass spectrometers deviate from the optimal condition because the velocity- and space-focusing conditions are considered separately for two ions with simplified equations. The result of a reexamination taking into account all essential ions reveals that the conventional ion source design, especially the length of the ion extraction region, results in poor resolving power. The comprehensive calculation demonstrates that the resolving power increases when the length of the extraction region is shorter than that of the conventional ion source. A numerical analysis indicates that the resolving power dramatically increases when the effective extraction potential compensates for the initial kinetic energy spread of ions. With typically used extraction potentials, the newly optimized ion source improves the resolving power by more than two orders of magnitude compared with the conventional design. This new theoretical interpretation can also be used to predict the optimal extraction potential and extraction delay in conventional ion sources to substantially improve the resolving power. This comprehensive calculation method is effective not only for designing new high-resolution instruments but also for optimizing commercial products.