## 1 Introduction  
Despite those great progresses achieved in improving precision and accuracy of analytical instruments, determination of analytes at trace level in complex matrices is still a huge challenge for direct instrumental analysis. At this time, the pretreatment step with the purpose of separation and/or enrichment of target analytes becomes a key prerequisite for accurate analysis. Even for high-sensitivity analyses, such as those employing liquid chromatograph-mass spectrometer/mass spectrometer (LC-MS/MS), proper sample preparation can be critical for minimizing matrix effects and concentrating analytes of interest [1, 2]. Among many pre-treatment methods, solid phase extraction has been widely used due to its high incidence rate, simple operation, low solvent consumption, and good reproducibility [3, 4, 5, 6, 7]. The principle of solid phase extraction is that the target analyte can be retained on the adsorbent by the interaction between them with the aim of enrichment and separation. According to the mode of interaction, the adsorbent can be roughly classified into two types, a single-mode adsorbent, and a mixed adsorbent [8, 9]. Single-mode adsorbents mainly include reversed phase, normal phase, and ion exchange adsorbents. The reversed phase and normal phase ones are often applied for retaining target analytes of non-polar, moderately polar to polar in the sample by hydrophobic interaction and polar interaction, respectively. Ion exchange adsorbent is mainly based on ion exchange interaction between the adsorbent and target analytes [10, 11, 12, 13, 14]. The disadvantage of single-mode adsorbents lies in that the mode of interaction is all the same for target analytes and other interferences. Thus, when the sample is very complex or contains many interference components, the performances in both removing interference components and obtaining good recoveries of target analytes are not optimistic. To solve the shortcomings of single-mode SPE, mixed-mode sorbents are designed to exhibit two or more primary interactions for the analyte retention, enabling greater cleanup selectivity and capacity of the extraction process. The combination of hydrophobic and ion exchange interactions is by far the most popular mixed mode, mainly including anion-exchange and cation-exchange mixed-mode sorbents, which have been used in highly efficient and selective extraction of acidic and basic compounds, respectively [15, 16]. Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most frequently used pain killer medicines, and NSAIDs cause toxicity in the environment even at very low concentration of ng L\({}^{-1}\) to ug L\({}^{-1}\). The presence of NSAIDs residues in natural water systems has raised major concerns for their potential risk to public health. Most NSAIDs contain a carboxylic acid group that can exist in protonated (neutral) state or in an ionized (charged) form. Therefore, mixed-mode SAX (SAX) sorbent such as Oasis MAX (pKa \(>\) 18) perform well in retaining and releasing weakly acidic NSAIDs at their deprotonation and protonation states, respectively. However, niflumic acid is a relatively strong acid (pKa = 1.68) that maintains ionization over the whole pH range investigated. As a result, mixed-mode SAX can be challenging as it is difficult to disrupt the ion-exchange interaction by only pH adjustment. Mixed-mode weak anion-exchange (WAX) sorbent with primary, secondary, and tertiary amine as functional groups introduces additional selectivity, which allows users to control the ionization of stationary phase by modifying the pH. In conclusion, mixed-mode SAX is for weakly acidic analytes while mixed-mode WAX is for strongly acidic analytes, since irreversible binding happens between a strong analyte and strong sorbent and it is difficult for weak sorbent to attract a weak analyte. Compared to silica-based sorbents, polymer-based sorbents have wide pH range and no silanol interactions exists [17].