# Solid Phase-Based Microextraction Techniques in Therapeutic Drug Monitoring
## 3 Sample Pretreatment--Solid Phase-Based Microextraction Techniques
### Microextraction by Packed Sorbent  
The MEPS procedure is a miniaturized version of the classic SPE technique, which was developed with the aim of reducing sample volume, organic extraction solvents and pretreatment time, without compromising extraction efficiency and allowing direct injection into gas (GC) and liquid (LC) chromatographic systems, due to the possibility of automation without any device modification [8; 9; 10; 11]. There are several sorbents used and commercially available for this technique, including silica matrices (unmodified silica, ethylsilane (C2), octylsilane (C8) and octadecylsilane (C18)), C18 strong cation/anion exchange (SCX, SAX), mixed sorbents (C8/SCX), polystyrene-divinylbenzene copolymers (PS/DVB), restricted access material (RAM) and MIPs [9; 10]. The extraction of analytes from the C2, C8 and C18 sorbents occurs via adsorption/hydrophobic van der Waals interactions and by electrostatic attraction and charge-charge Coulomb interaction for SCX and SAX sorbents. The RAM phases simultaneously present size exclusion with hydrophobic and ion-exchange extraction interactions, and the hydrophobic structure of the PS-DVB interacts with the analytes via van der Waals forces and \(\pi\)-\(\pi\) interactions of the aromatic rings. Interactions for MIPs are similar to those between antibodies and antigens, consisting in electrostatic and hydrophobic interactions, hydrogen bonds and van der Waals forces [12; 13; 14]. This technique combines sample extraction, pre-concentration and cleaning in a single device, and it is considered more environmentally friendly compared to conventional approaches [8; 9; 10; 15]. Normally, a MEPS protocol follows a four-step procedure: conditioning of the sorbent, sample loading, washing and analyte elution. These steps consist of cycles of ascending and descending movements of the solutions through the sorbent, and all the stages and solvents used can be optimized in order to obtain better efficiency and recovery results of the analytes under study. In addition, other conditions such as sorbent selection, pH of the working solution and ionic strength must be optimized to reduce possible interferences, matrix effects and carry-over [9; 10]. Table 1 indicates some of the advantages and disadvantages of this technique [9; 11]. MEPS has been applied for the extraction of many drugs and metabolites from biological specimens, and Table 2 summarizes the bioanalytical procedures published between 2017 and 2022 which use MEPS for TDM. \begin{table}
\begin{tabular}{c c c c} \hline
**Extraction** & & **Advantages** & **Disadvantages** \\
**Technique** & & & \\ \hline \multirow{6}{*}{MEPS} & - & Simple and broad (works with & \\  & & several ranges of analytes and & \\  & & matrices); & \\ \cline{1-1}  & - & Environmentally friendly (uses low & - \\ \cline{1-1}  & & sample volumes and organic & - \\ \cline{1-1}  & & solvents); & \\ \cline{1-1}  & - & Sorbents can be re-used several & - \\ \cline{1-1}  & & times, therefore the cost per & \\ \cline{1-1}  & & analysis is lower; & \\ \cline{1-1}  & - & Possibility of automation. & \\ \hline \end{tabular}
\end{table} 
Table 1: Advantages and disadvantages of the MEPS procedure. \begin{table}
\begin{tabular}{c c c c c c c} \hline \hline
**Analyves** & **Sample (Amount)** & **Sample Pretreatment and Extraction Procedure** & **Analytical Technique** & **LOD; LOQ** & **Linear Range** & **Ref.