## 3 Analytical Instrumentation
### Mass Spectrometry: Interfaces and Analysers
During the ionization by electrospray, three kinds of ions are formed: molecular ions, protonated and deprotonated species, and adducts. The extent to which each of these ions is formed can be understood in terms of the balance between three essentially different processes, which occur inside the capillary: redox reactions (oxidation/reduction), which produce molecular ions, acid/base reactions (protonation/deprotonation), which result in the formation of protonated or deprotonated species, and coordination with cations (usually alkali metals) or anions (mainly chlorides), which leads to the formation of adducts. The ionization of most PhACs generally occurs through acid-base reactions since their redox potentials are low. In the case where the formation of ions is carried out by protonation/deprotonation, the pKa of the functional groups of the analytes is one of the main factors that influence the ionization process. In general, the alkaline compounds are ionized in the positive mode, giving rise to protonated ions at low pH values, and the acidic compounds ionize in the negative mode suffering deprotonation at high pH [193]. Single quadrupole mass spectrometry [90; 176; 194], especially tandem mass spectrometry (MS/MS) with triple quadrupole detection [10; 46; 10; 126; 132; 195], QTOF (quadrupole-time of flight) [173; 196], and quadrupole-ion-trap [91; 197], have been the most used techniques in recent years, due to their high sensitivity and selectivity. The tandem mass spectrometry (MS/MS) has been considered to be an identification and confirmation tool. The monitoring of the fragments provides more excellent discrimination than a single quadrupole (MS). This approach has several advantages, as it reduces the excessive sample preparation steps, decreases false positive and negative results in complex samples, allows for the identification of analytes with different physical-chemical characteristics at ultra-trace levels, results in less time and cost of analysis due to the reduced amount of reagents used in sample preparation and provides better detectability and selectivity. Up to date, the residue analysis of PhACs in waters has been accomplished by LC-MS/MS in the selected reaction monitoring (SRM) mode or multiple reaction monitoring (MRM). The SRM mode has a severe limitation--the number of compounds that can be screened in a single run [86]. Up to 150-200 compounds (depending on the scan speed/dwell-time) can be analyzed in a run by LC-MS/MS in the SRM mode with a dedicated chromatographic method. Besides, when increasing the number of compounds included in the SRM method, the possibility of finding common or overlapped transitions for coeluting isobaric compounds increases. Another major limitation of these SRM methods is that they are blind to compounds not defined in the SRM method (non-target analysis). None or scarce information on possible non-target/unknown organic micro-contaminants or their degradation products is available when using these techniques [37]. Several hybrid systems have been used in the monitorization of PhACs in water matrices. [PERSON] et al. [37] monitored 81 target compounds (PhACs and their metabolites)in wastewater influent and effluent, river, reservoir, sea, and tap waters using an ultra-high-performance liquid chromatography that was coupled to quadrupole linear ion trap tandem mass spectrometry (UPLC-QqLIT). The PhACs belong to 19 therapeutical classes. The main therapeutical classes under analysis were psychiatric drugs (15 compounds) and antibiotics (13 compounds). The method yielded detection limits between 0.04-20 ng/L in sea waters and 0.7-140 ng/L in wastewater influents. Thus, it is providing a reliable and robust tool that can be used for the routine analysis of multiple-class pharmaceuticals in aqueous samples. UPLC technology allowed for a fast separation of many pharmaceuticals, with improved sensitivity, altogether with a significant cost reduction in terms of time per analysis and solvent consumption.