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| Ionization techniques in mass spectrometry coupled to separations techniques |
| Type of MS analysis | Advantages | Disadvantages | References |
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| Negative chemical ionization | (i) It provides more sensitivity at low concentration (pg) based on the stability of electronegative moieties. | (i) Better results are provided when the technique is combined with EI-MS in order to obtain more structural information. | [14] |
| (ii) Avoids wrong interpretations of correct results reducing time consumption. | (ii) This method requires an additional reagent for the ionization; methane is commonly used. |
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| Cold electrospray ionization | (i) It can be considered as a miniaturized analytical method because of the interface that it uses and the supersonic molecular beams through analysis with short columns and high column flow rates. | (i) Additional instrumentation is required. | [15, 16] |
| (ii) Can provide enhanced molecular ions to much larger and more polar compounds with GC, using the same library to EI-MS (NIST). |
| (iii) The flow rate can be increased up to 100 mL/min, and its fly-through ion source sensitivity is fully independent from the column flow rate. |
| (iv) In this method, the nozzle flow rate is constant; as a result, the cold EI fly-through ion source is unaffected by the column flow rate, unlike any other ion source. |
| (v) The use of GC-MS with cold EI has no limitations for the column used. |
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| Surface-activated chemical ionization | (i) The ionization of solutes occurs upon the polarization of neutral, solvent molecules, which makes it a highly sensitive method. | (i) SACI is used to maximize the sensitivity in the analysis of highly polar compounds, but data about less polar compounds have not been revealed until now. | [17] |
| (ii) The electrostatically charged surface increases the ESI ionization efficiency. |
| (iii) When it is used with ESI, the efficiency of proton-transfer ionization reactions is enhanced by the polarization of neutral solvent molecules or by charged solute molecules induced by the proximity of the charged surface. |
| (iv) The solvent and the analyte ions are better focused towards the analyzer. |
| (v) The increase in signal intensity provides an increase in sensitivity, because there is a reduction in the chemical noise observed in the mass analyzer. |
| New methods of analysis used in mass spectrometry |
| Dynamic multiple reaction monitoring mode of analysis | (i) This method monitors the analytes only around the expected retention time, decreasing the number of concurrent MRM transitions, allowing both the cycle and the dwell time, which can be optimized in order to obtain higher sensitivity, accuracy, and reproducibility. | (i) It is necessary to maintain the analyte analysis in the same polar mode since a switch of polarity within a single run would reduce the sensitivity and accuracy of quantification with the applied MS instrumentation. | [17–20] |
| (ii) dMRM allows the monitoring of more MRM transitions in a single run without compromising data quality. | (ii) The retention time must be informed, optimized, and defined with reference standards using established chromatographic conditions if it is possible. If the retention time drifts, this might result in an incomplete peak definition and quantitation. |
| (iii) The dwell time is intelligently optimized by association with the delta retention time. Additionally, information about delta retention time and retention time are key to maximize the dwell time and increasing sensitivity. | (iii) It is necessary to optimize the MS conditions for the all transitions. |
| (iv) This method gives the possibility of applying simultaneous quantifications of multiple components. |
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| Ambient ionization techniques in mass spectrometry |
| Desorption electrospray ionization-mass spectrometry | (i) Direct analysis with high-velocity nebulizing gas. | (i) During analysis of drugs in biological matrix with a high amount of salt, the suppression ionization effect is elevated. | [8, 21–23] |
| (ii) The selectivity and sensitivity of this technique can be increased by a pretreatment sample. | (ii) The ion source geometry affects the dynamic of the splashing mechanism resulting in changes in droplet size, charge, and analyte dissolution extent. |
| (iii) A high velocity of nebulization can mechanically ablate delicate samples/powders. |
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| Desorption atmospheric-pressure photoionization | (i) Matrix with high salt content do not provide an elevated suppression of ionization. | (i) High suppression ionization can be found depending of the biological matrix. | [8, 21–25] |
| (ii) Sample preparation is commonly needed in order to avoid suppression of ionization. |
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| Direct analysis in real time | (i) It is commonly used in the analysis of drugs of low molecular weight; therefore, its sensitivity depends on analyte volatility. | (i) Compounds of high molecular weight may need derivatization. | [4, 8, 11, 26–35] |
| (ii) The geometrical configuration of the ion source is simple and robust for its operation. | (ii) Its sensitivity depends of the temperature of the ionization region; therefore, the higher the temperature is the higher the risk of damage is. |
| (iii) Pretreatment of sample can increase the selectivity of the analysis in complex biological samples. | (iii) Its reproducibility depends on the position of the sample inside the ion source, which represents a big problem in the quantification of the analysis. |
| Low-temperature plasma | (i) It is possible to perform direct analysis without sample preparation. | (i) This technique is exclusively used with small organic molecules with low to moderate polarity. | [8, 36] |
| (ii) The instrumentation is simple, and its configuration provides low consumption of discharge gas and the possibility of using air as the discharge gas. |
| (iii) High sensitivity and sensitivity can be obtained without pretreatment of the samples. |
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| Matrix-assisted laser desorption electrospray ionization | (i) It can be coupled to mass spectrometric imaging (MSI) in order to obtain the distribution spectra of the target. | (i) Quantitative analysis has not been carried out until this present date. | [8, 37–41] |
| (ii) A mode of analysis called “dynamic pixel” can be used to obtain an imaging method that is faster to do a screening of the compounds. |
| (iii) The analysis does not need sample preparation. This method is based on a direct analysis over the sample. |
| (iv) The sensitivity of the analysis can be improved using a specific matrix. For example, umbelliferone matrix obtained better results in the analysis of methamphetamine in hair than the common matrices CHCA or DHB. |
| (v) The technique has been tested along with MAMS, and it is possible to cause reproducibility of the signal with this technology. |
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| Metal-assisted secondary ion mass spectrometry | (i) It can be coupled to mass spectrometric imaging (MSI) in order to obtain the distribution spectra of the target. | (i) Quantitative analysis has not been carried out. | [8, 42, 43] |
| (ii) The limits of detection are lower than those obtained with MALDESI and also compared with the ones with LC-MS/MS. |
| (iii) It is not necessary to perform preparation of the sample. |
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| Paper spray | (i) This technique can analyze a wide range of molecules, from small to large biomolecules. | (i) It has a high matrix effect on most of the drugs. | [8, 44–51] |
| (ii) The use of a pretreatment of the sample can enhance the sensitivity of the analysis. | (ii) The paper can extract impurities from the surface and cause the suppression of ionization. |
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| High-performance ion mobility spectrometry | (i) Methods of introduction of samples such as a chromatographic separation can be used to minimize the suppression of ionization. | (i) Direct analysis can result in suppression of ionization. | [50, 51] |
| Differential mobility spectrometry-mass spectrometry separation | (i) Separation conditions of the target analysis can be selectively transmitted into a mass spectrometer. | (i) This technique is rarely being implemented in commercial devices, and it is not known yet whether it can be used to establish profiles of drug mixtures in complex biological samples. | [52] |
| (ii) It can be considered as an ionization technique coupled to a separation method that has a small interface which gives results in few seconds. |
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| Touch spray | (i) The substrate (medical swabs) used can serve as a sample collection tool; thus, ionization helps in the analysis of solid or liquid samples without pretreatment. | (i) The drying step of this substrate represents the most time-consuming part of the analytical protocol. | [9] |
| (ii) The TS-MS can allow noninvasive and direct sampling of neat oral fluids. |
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| Laser diode thermal desorption | (i) The method is completely automatic. | (i) It is not possible to perform a simple interchange between negative and positive modes of ionization. | [53] |
| (ii) Effects of interferences in complex biological samples must be explored, and more sample preparation is necessary before the liquid samples are transferred towards the capillary surface. |
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| Atmospheric solids probe analysis | (i) It is possible to perform analysis of solids and liquids easily. | (i) Effects of interferences in complex biological samples must be explored with more detail. | [53, 54] |
| (ii) This design allows the possibility of positive/negative switch during the analysis. | (ii) This technique provides better sensitivity during the analysis of small-molecule drugs, decreasing the analysis of the high-molecule compounds. |
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