Atmospheric-pressure chemical ionization

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Atmospheric pressure chemical ionization chamber cross section Atmospheric pressure chemical ionization chamber.jpg
Atmospheric pressure chemical ionization chamber cross section

Atmospheric pressure chemical ionization (APCI) is an ionization method used in mass spectrometry which utilizes gas-phase ion-molecule reactions at atmospheric pressure (105 Pa), [1] [2] commonly coupled with high-performance liquid chromatography (HPLC). [3] APCI is a soft ionization method similar to chemical ionization where primary ions are produced on a solvent spray. [4] The main usage of APCI is for polar and relatively less polar thermally stable compounds with molecular weight less than 1500 Da. [5] The application of APCI with HPLC has gained a large popularity in trace analysis detection such as steroids, pesticides and also in pharmacology for drug metabolites. [6]

Contents

Instrument structure

APCI source with heated nebulizer LC inlet APCI Source With Heated Nebulizer.png
APCI source with heated nebulizer LC inlet

A typical APCI source usually consists of three main parts: a sample inlet, a corona discharge needle, and an ion transfer region under intermediate pressure. [5] In the case of the heated nebulizer inlet [7] from an LC, as shown in the figure, the eluate flows at 0.2 to 2.0 mL/min into a pneumatic nebulizer which creates a mist of fine droplets. Droplets are vaporized by impact with the heated walls at 350–500 °C and carried by the nebulizer gas and an auxiliary gas into the ion molecule reaction region between the corona electrode and the exit counter-electrode. [4] A constant current of 2–5 microamps is maintained from the corona needle. Sample ions are produced by ion-molecule reactions (as described below), and pass through a small orifice or tube into the ion transfer region leading to the mass spectrometer.

Various geometries of ion source are possible, depending on application. When used with liquid chromatography, particularly at higher flow rates, the nebulizer is often positioned orthogonal to (or at a similarly steep angle to) the inlet of the mass spectrometer, so that solvent and neutral material does not contaminate the actual inlet of the mass spectrometer. [8]

Atmospheric pressure chemical ionization (APCI) spray chamber from LC-MS; this ion source (spray chamber) would fit onto a mass spectrometer on the side facing the viewer, with the mass spectrometer's inlet at roughly the level of the corona discharge needle Agilent APCI annotated.jpg
Atmospheric pressure chemical ionization (APCI) spray chamber from LC-MS; this ion source (spray chamber) would fit onto a mass spectrometer on the side facing the viewer, with the mass spectrometer's inlet at roughly the level of the corona discharge needle

Ionization mechanism

Ionization in the gas phase by APCI follows the sequences: sample in solution, sample vapor, and sample ions. The effluent from the HPLC is evaporated completely. The mixture of solvent and sample vapor is then ionized by ion-molecule reaction. [9]

The ionization can either be carried out in positive or negative ionization mode. In the positive mode, the relative proton affinities of the reactant ions and the gaseous analyte molecules allow either proton transfer or adduction of reactant gas ions to produce the ions [M+H]+ of the molecular species. [4] In the negative mode, [M−H]− ions are produced by either proton abstraction, or [M+X]− ions are produced by anion attachment. Most work on the APCI-MS analysis has been in positive mode.

In the positive mode, when the discharge current of corona discharge is 1-5 μA on the nebulized solvent, N2 gas molecules are excited and ionized, which produce N4+*. The evaporated mobile phase of LC acts as the ionization gas and reactant ions. If water is the only solvent in the evaporated mobile phase, the excited nitrogen molecular ions N4+* would react with H2O molecules to produce water cluster ions H+(H2O)n. [10] Then, analyte molecules M are protonated by the water cluster ions. Finally, the ionization products MH+(H2O)m transfer out from the atmospheric-pressure ion source. Declustering (removal of water molecules from the protonated analyte molecule) of MH+(H2O)m takes place at the high vacuum of the mass analyzer. [2] The analyte molecule ions detected by MS are [M+H]+. The chemical reactions of ionization process are shown below.

Primary and secondary reagent ion formation in a nitrogen atmosphere in the presence of water: [11] [2]

N2 + e → N2+ + 2e
N2+* + 2N2 → N4+* + N2
N4+ + H2O → H2O+ + 2N2
H2O+ + H2O → H3O+ + OH•
H3O+ + H2O + N2 → H+(H2O)2 + N2
H+(H2O)n-1 + H2O + N2 → H+(H2O)n + N2

Ionization of product ions: [2]

H+(H2O)n + M → MH+(H2O)m + (n-m)H2O

Declustering in the high vacuum of the mass analyzer: [2]

MH+(H2O)m → MH+ + mH2O

If the mobile phase contains solvents with a higher proton affinity than water, proton-transfer reactions take place that lead to protonated the solvent with higher proton affinity. For example, when methanol solvent is present, the cluster solvent ions would be CH3OH2+(H2O)n(CH3OH)m. [2] Fragmentation does not normally occur inside the APCI source. If a fragment ion of a sample is observed, thermal degradation has taken place by the heated nebulizer interface, followed by the ionization of the decomposition products.

In a major distinction from chemical ionization, the electrons needed for the primary ionization are not produced by a heated filament, as a heated filament cannot be used under atmospheric pressure conditions. Instead, the ionization must occur using either corona discharges or β- particle emitters, which are both electron sources capable of handling the presence of corrosive or oxidizing gases. [4]

History

The origins of atmospheric pressure chemical ionization sources combined with mass spectrometry can be found in the 1960s in studies of ions in flames [12] and of ion chemistry in corona discharges up to atmospheric pressure. [13] The first application of APCI combined with mass spectrometry for trace chemical analysis was by the Franklin GNO Corporation who in 1971 developed an instrument combining APCI with ion mobility and mass spectrometry. [14] Horning, Carroll and their co-workers in the 1970s at the Baylor College of Medicine (Houston, TX) demonstrated the advantages of APCI for coupling gas chromatography (GC) [15] and liquid chromatography (LC) [16] to a mass spectrometer. High sensitivity and simple mass spectra were shown in these studies. [16] For LC-MS, the LC eluate was vaporized and ionized in a heated metal block. Initially, a 63Ni foil was used as a source of electrons to perform ionization. In 1975, a corona discharge electrode was developed, providing a larger dynamic response range. [17] APCI with the corona discharge electrode became the model for modern commercially available APCI interfaces. [18]

In the late 1970s an APCI mass spectrometer system (the TAGA, for Trace Atmospheric Gas Analyzer), mounted in a van for mobile operation, was introduced by SCIEX, [19] [20] providing high sensitivity for monitoring polar organics in ambient air in real time. In 1981 a triple quadrupole mass spectrometer version was produced, allowing real-time direct air monitoring by APCI-MS/MS. A similar platform was used for the SCIEX AROMIC system (part of the CONDOR contraband detection system developed together with British Aerospace) for the detection of drugs, explosives and alcohol in shipping containers at border crossings, by sampling the interior airspace. [21] [22]

In the mid-1980s and into the early 1990s, the advantages of performing LC/MS with APCI and with electrospray, both atmospheric pressure ionization techniques, began to capture the attention of the analytical community. [3] Together they have dramatically expanded the role of mass spectrometry in the pharmaceutical industry for both drug development and drug discovery applications. The sensitivity of APCI combined with the specificity of LC-MS and LC-MS/MS often makes it the method of choice for the quantification of drugs and drug metabolites. [23]

Advantages

Ionization of the substrate is very efficient as it occurs at atmospheric pressure, and thus has a high collision frequency. Additionally, APCI considerably reduces the thermal decomposition of the analyte because of the rapid desolvation and vaporization of the droplets in the initial stages of the ionization. [4] This combination of factors most typically results in the production of ions of the molecular species with fewer fragmentations than many other ionization methods, making it a soft ionization method. [24]

Another advantage to using APCI over other ionization methods is that it allows for the high flow rates typical of standard bore HPLC (0.2–2.0 mL/min) to be used directly, often without diverting the larger fraction of volume to waste. Additionally, APCI can often be performed in a modified ESI source. [25] The ionization occurs in the gas phase, unlike ESI, where the ionization occurs in the liquid phase. A potential advantage of APCI is that it is possible to use a nonpolar solvent as a mobile phase solution, instead of a polar solvent, because the solvent and molecules of interest are converted to a gaseous state before reaching the corona discharge needle. Because APCI involves a gas-phase chemistry, there is no need to use special conditions such as solvents, conductivity, pH for LC. APCI appears to be more versatile LC/MS interface and more compatible with reversed-phase LC than ESI. [24]

Application

APCI is suited for thermal stable samples with low to medium (less than 1500 Da) molecular weight, and medium to high polarity. It is particularly useful for analytes that are not sufficiently polar for electrospray. The application area of APCI is the analysis of drugs, nonpolar lipids, natural compounds, pesticides and various organic compounds, but it is of limited use in the analysis of biopolymers, organometallics, ionic compounds and other labile analytes. [26]

See also

Related Research Articles

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<span class="mw-page-title-main">Ion source</span> Device that creates charged atoms and molecules (ions)

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<span class="mw-page-title-main">Electrospray ionization</span> Technique used in mass spectroscopy

Electrospray ionization (ESI) is a technique used in mass spectrometry to produce ions using an electrospray in which a high voltage is applied to a liquid to create an aerosol. It is especially useful in producing ions from macromolecules because it overcomes the propensity of these molecules to fragment when ionized. ESI is different from other ionization processes since it may produce multiple-charged ions, effectively extending the mass range of the analyser to accommodate the kDa-MDa orders of magnitude observed in proteins and their associated polypeptide fragments.

<span class="mw-page-title-main">Chemical ionization</span> Ionization technique used in mass [[spectroscopy]]

Chemical ionization (CI) is a soft ionization technique used in mass spectrometry. This was first introduced by Burnaby Munson and Frank H. Field in 1966. This technique is a branch of gaseous ion-molecule chemistry. Reagent gas molecules are ionized by electron ionization to form reagent ions, which subsequently react with analyte molecules in the gas phase to create analyte ions for analysis by mass spectrometry. Negative chemical ionization (NCI), charge-exchange chemical ionization, atmospheric-pressure chemical ionization (APCI) and atmospheric pressure photoionization (APPI) are some of the common variants of the technique. CI mass spectrometry finds general application in the identification, structure elucidation and quantitation of organic compounds as well as some utility in biochemical analysis. Samples to be analyzed must be in vapour form, or else, must be vapourized before introduction into the source.

<span class="mw-page-title-main">Liquid chromatography–mass spectrometry</span> Analytical chemistry technique

Liquid chromatography–mass spectrometry (LC–MS) is an analytical chemistry technique that combines the physical separation capabilities of liquid chromatography with the mass analysis capabilities of mass spectrometry (MS). Coupled chromatography – MS systems are popular in chemical analysis because the individual capabilities of each technique are enhanced synergistically. While liquid chromatography separates mixtures with multiple components, mass spectrometry provides spectral information that may help to identify each separated component. MS is not only sensitive, but provides selective detection, relieving the need for complete chromatographic separation. LC–MS is also appropriate for metabolomics because of its good coverage of a wide range of chemicals. This tandem technique can be used to analyze biochemical, organic, and inorganic compounds commonly found in complex samples of environmental and biological origin. Therefore, LC–MS may be applied in a wide range of sectors including biotechnology, environment monitoring, food processing, and pharmaceutical, agrochemical, and cosmetic industries. Since the early 2000s, LC–MS has also begun to be used in clinical applications.

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<span class="mw-page-title-main">Thermospray</span>

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<span class="mw-page-title-main">Desorption electrospray ionization</span>

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<span class="mw-page-title-main">Two-dimensional chromatography</span>

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<span class="mw-page-title-main">Desorption atmospheric pressure photoionization</span>

Desorption atmospheric pressure photoionization (DAPPI) is an ambient ionization technique for mass spectrometry that uses hot solvent vapor for desorption in conjunction with photoionization. Ambient Ionization techniques allow for direct analysis of samples without pretreatment. The direct analysis technique, such as DAPPI, eliminates the extraction steps seen in most nontraditional samples. DAPPI can be used to analyze bulkier samples, such as, tablets, powders, resins, plants, and tissues. The first step of this technique utilizes a jet of hot solvent vapor. The hot jet thermally desorbs the sample from a surface. The vaporized sample is then ionized by the vacuum ultraviolet light and consequently sampled into a mass spectrometer. DAPPI can detect a range of both polar and non-polar compounds, but is most sensitive when analyzing neutral or non-polar compounds. This technique also offers a selective and soft ionization for highly conjugated compounds.

<span class="mw-page-title-main">Ambient ionization</span>

Ambient ionization is a form of ionization in which ions are formed in an ion source outside the mass spectrometer without sample preparation or separation. Ions can be formed by extraction into charged electrospray droplets, thermally desorbed and ionized by chemical ionization, or laser desorbed or ablated and post-ionized before they enter the mass spectrometer.

<span class="mw-page-title-main">Direct electron ionization liquid chromatography–mass spectrometry interface</span>

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<span class="mw-page-title-main">Atmospheric pressure photoionization</span> Soft ionization method

Atmospheric pressure photoionization (APPI) is a soft ionization method used in mass spectrometry (MS) usually coupled to liquid chromatography (LC). Molecules are ionized using a vacuum ultraviolet (VUV) light source operating at atmospheric pressure, either by direct absorption followed by electron ejection or through ionization of a dopant molecule that leads to chemical ionization of target molecules. The sample is usually a solvent spray that is vaporized by nebulization and heat. The benefit of APPI is that it ionizes molecules across a broad range of polarity and is particularly useful for ionization of low polarity molecules for which other popular ionization methods such as electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) are less suitable. It is also less prone to ion suppression and matrix effects compared to ESI and APCI and typically has a wide linear dynamic range. The application of APPI with LC/MS is commonly used for analysis of petroleum compounds, pesticides, steroids, and drug metabolites lacking polar functional groups and is being extensively deployed for ambient ionization particularly for explosives detection in security applications.

<span class="mw-page-title-main">Matrix-assisted ionization</span>

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<span class="mw-page-title-main">Laser diode thermal desorption</span>

Laser diode thermal desorption (LDTD) is an ionization technique that is coupled to mass spectrometry to analyze samples with atmospheric pressure chemical ionization (APCI). It uses a laser to thermally desorb analytes that are deposited on a stainless steel sheet sample holder, called LazWell. The coupling of LDTD and APCI is considered to be a soft-ionization technique. With LDTD-APCI, it is possible to analyze samples in forensics, pharmaceuticals, environment, food and clinical studies. LDTD is suitable for small molecules between 0 and 1200 Da and some peptides such as cyclosporine.

SCIEX is a manufacturer of mass spectrometry instrumentation used in biomedical and environmental applications. Originally started by scientists from the University of Toronto Institute for Aerospace Studies, it is now part of Danaher Corporation with the SCIEX R&D division still located in Toronto, Canada.

References

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  18. ↑ Byrdwell, William Craig (2001-04-01). "Atmospheric pressure chemical ionization mass spectrometry for analysis of lipids". Lipids. 36 (4): 327–346. doi:10.1007/s11745-001-0725-5. ISSN   0024-4201. PMID   11383683. S2CID   4017177.
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  24. 1 2 Zaikin, Vladimir G.; Halket, John M. (2017). "Derivatization in Mass Spectrometry—8. Soft Ionization Mass Spectrometry of Small Molecules". European Journal of Mass Spectrometry. 12 (2): 79–115. doi:10.1255/ejms.798. ISSN   1469-0667. PMID   16723751. S2CID   34838846.
  25. ↑ Holčapek, Michal; Jirásko, Robert; Lísa, Miroslav (2012). "Recent developments in liquid chromatography–mass spectrometry and related techniques". Journal of Chromatography A. 1259: 3–15. doi:10.1016/j.chroma.2012.08.072. ISSN   0021-9673. PMID   22959775.
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