# Solid Phase-Based Microextraction Techniques in Therapeutic Drug Monitoring
## 3 Sample Pretreatment--Solid Phase-Based Microextraction Techniques
### Solid-Phase Microextraction and in-Tube Solid-Phase Microextraction  
SPME is a popular and innovative solventless extraction technique that is used, for instance, in the pharmaceutical, forensic and environmental areas. This technique combines sampling, extraction and injection of samples into an analytical system, and, although it is not an exhaustive process, all the analyte obtained from the extraction is introduced into chromatography [25]. This technique uses fused silica fibers covered by a stationary phase (liquid or solid) in a syringe that will be exposed to a sample; an equilibrium will then be established between the sample and the sorbent, operated either by direct extraction, headspace extraction or membrane-protected extraction [25; 26]. There are several coatings used for this technique, including polydimethylsiloxane (PDMS), polyacrylamide (PA), divinylbenzene (DVB), PDMS/DVB, carbowax/DVB, PDMS/carboxen (CAR), carbowax/templated resin, DVB/CAR/PDMS, MIPs and RAM. SPME fibers can be categorized into two main groups, adsorbents or absorbents, depending on the type of collection process; the examples given above represent the first case, presenting van der Waals or hydrogen bonds interactions. The large implementation of SPME in laboratories leads to the creation of different types of fiber for different uses of this extraction technique, which is applicable to solid, liquid and gaseous samples, allowing for lower solvent consumption, simplification of sample preparation and a shorter extraction time [25; 26; 27; 28]. In contrast to the above-mentioned, in-tube SPME uses a capillary tube, of <1 mm internal section, usually coated with fused silica. However, fiber-packed, sorbent-packed and rod-type monolith capillaries are available as well [29]. In order to improve efficiency and specificity, the analytes in this technique are absorbed or adsorbed on the outer surface of the packing material. Able to operate as a flow-through or as a draw/eject extraction system, the analysis can be performed online or offline by LC or GC, after desorption of the extracted compounds via a mobile phase flow or a static desorption solvent. This technique can also be automated [28; 30; 31]. Table 3 summarizes some of the advantages and disadvantages of these two techniques [25; 26; 32]. Table 4 contains bioanalytical procedures published between 2020 and 2022 (SPME), and published between 2010 and 2022 (in tube-SPME) concerning TDM. \begin{table}
\begin{tabular}{c c c c} \hline \hline
**Extraction** & & **Advantages** & & **Disadvantages** \\ \hline \multirow{6}{*}{SPME and in-tube SPME} & \multirow{2}{*}{-} & Simple and solvent-free extraction & - & Limitation on the chemical nature of the stationary phase on the market; \\  & & method; & & on the market; \\  & - & Reduces solvent consumption & - & Competition between drug and endogenous compounds for the fiber; \\  & & and time extraction since all the & & and endogenous compounds \\  & & extracted material can be directly & & for the fiber; \\  & - & Extracting device is portable and & - & Fibers are fragile materials, leading to breakage and \\  & - & Allows field sampling; & coating stripping, limiting \\  & - & Possibility of automation. & - & Not-exhaustive method. \\ \hline \hline \end{tabular}
\end{table} 
Table 3: Advantages and disadvantages of the SPME and in-tube SPME procedures. \begin{table}
\begin{tabular}{c c c c c c c c} \hline \hline
**Analytes** & **Sample (Amount)** & **Sample Pretreatment and Extraction Procedure** & **Analytical Technique** & **LOD; LOQ** & **Linear Range** & **Ref. ** \\ \hline \multirow{4}{*}{Rifampicic} & Protein precipitation with acetonitrile at a 21 \(\mu\)m (_vs_), agitation and centrifugation; the supernatant is collected, dried, resuspended on 55 mL of buffer sodium and & & & & \\  & 500 mL of plasma & vortexed. In-tube SME extraction is performed with 10 \(\mu\)m/ml.