**6. Analytical applications**

irradiation than non-imprinted photo catalyst [53]. Molecular imprinting magnetic γ-Fe2

0.11 ng.mL−1 (S/N = 3), without any matrix effect, cross-reactivity and false-positives.

Diclofenac Methanol/acetic acid (9:1, v:v) 30 binding/regeneration cycles with ≥95%

Multi-templates\* Methanol/acetic acid (9:1, v/v) 20 adsorption and desorption cycles gave

Multi-templates were ibuprofen, naproxen, ketoprofen, diclofenac and clofibric acid.

MIPs sorbents are easily regenerated by washing with organic solvents to remove the adsorbed compounds. Therefore, they can be applied for various extractions repeatedly. In this aspect, acetylsalicylic acid MIP successfully adsorbed (removal efficiency 75–78%) the target compound from acidic aqueous solutions six times [55]. After desorption, MIP was regenerated with a mixture of methanol and acetic acid (7:3, v/v) followed by methanol. There are numerous examples of reusability in literature that include those cited in **Table 3** for the MIPs prepared for selective extraction of acetylsalicylic acid [55], diclofenac [36] and multitemplates (ibuprofen, naproxen, ketoprofen, diclofenac and clofibric acid) [26]. Such work, clearly demonstrate that MIP can be reused many times without losing its adsorption capacity. This is an excellent advantage for MIP as it is a common knowledge that many adsorbents

**Regeneration solvent Successful applications Reference**

constant recovery (≥95%)

recovery

with 75–78% removal efficiency

6 repeatable adsorption/desorption experiments

[55]

[36]

[26]

**5. Reusability**

58 Recent Research in Polymerization

are discarded after a single use.

**Table 3.** Examples for reusability of MIPs.

Acetylsalicylic acid Methanol/acetic acid (7:3, v/v) and methnol

**Template/target compound**

\*

cross-linked chitosan composites prepared by a microemulsion process were applied for the adsorption and degradation of norfloxacin (NOR) [48]. The MIP showed superior adsorption of NOR than its non-imprinted counterpart [48] and excellent selectivity of NOR adsorption in comparison to sulfadiazine, ofloxacin and phenol [49]. Elsewhere, an electrochemical sensor constructed by grafting MIP to multi-walled carbon nanotube (MWCNTs) surface immobilized on glass carbon electrode was evaluated for the determination of ceftazidime from human serum [51]. The functionalized MWCNTs played two roles, increasing the conductivity of a sensor and the amount of binding sites. The sensor demonstrated good precision, stability, sensitivity and selectivity for the target analyte. Recent work showed the synthesis of polymer composites for pharmaceutical drugs, where such materials are prepared for the purpose of sensory applications [52]. Prasad et al. [52] synthesized a novel monomeric graphene quantum dots—MIP-based nanocomposite directly at the surface of screen printed carbon electrode and applied for electrochemical detection of an anticancerous drug ifosfamide in biological and pharmaceutical samples. Their sensor gave the detection limit of

O3 /

> In relation with pharmaceutical compounds, MIPs are used in analytical applications such as sample preparation as SPE sorbents [37], chromatographic stationary phase [56] and biological sensing [51]. The analytical applications of MIPs are very useful for various reasons, such as they provide higher selectivity than the conventional sorbents, they also reduce the matrix influence on the resulting chromatograms and they lead to high sample enrichment factors [57]. Besides the use of MIPs in analytical applications such as sample preparation, they are widely evaluated as selective adsorbents in contaminated water. MIPs are introduced as clean-up adsorbents in environmental waters for removal of pharmaceuticals (batch adsorption) [31, 55].

#### **6.1. Sample preparation**

Sample preparation for the determination of pharmaceuticals in aqueous samples is, in most cases, preceded by a filtration method prior to pre-concentration [58]. However, this step may lead to loss of some compounds bound to particulate matter. Typical example to this, is the detection of trace levels of mefenamic acid (a hydrophobic compound) at μg.kg−1 on the suspended solids following filtration [59]. Therefore, removal efficiencies and mass loadings may be affected by the filtration step [58]. Solid-phase extraction (SPE) techniques, on the other hand, have shown fairly good pre-concentration and extraction efficiencies for hydrophobic compounds. However, commercial reversed phase-based adsorbents used in SPE have not shown satisfactory efficiencies for the pre-concentration of polar organic compounds. It has been suggested that the molecular recognition brought about by MIPs could address this downfall of SPE [58]. Instead of conventional sorbents, the SPE cartridges are in this case packed with MIP particles. That is, the synthesized MIP particles are slurry or dry packed in between two frits inside the solid-phase extraction cartridge [60, 61], referred to as MISPE. After packing, the cartridge is then conditioned prior to the loading of sample solutions. Thereafter, the MISPE cartridge is washed for removal of sample interferences and the target compounds are eluted with a suitable organic solvent. MISPE has been widely used for selective extraction of pharmaceuticals from various matrices that include plasma, urine and water samples [25, 57, 62]. In most cases, MISPE is applied where target compounds are extracted from solution into the solid material.

In addition, other mode of solid-phase extraction for ARV drug (abacavir) such as solid-phase microextraction (SPME) has been reported [63]. The molecularly imprinted SPME technology for drug analysis has been described in great details by Ansari and Karimi [22]. These authors focussed on the progress, challenges and trends in trace determination of different drugs.

#### *6.1.1. Molecularly imprinted solid-phase extraction*

Pharmaceuticals from different classes have been extracted and pre-concentrated using MISPE (**Table 4**). Most common non-steroidal anti-inflammatory drugs (NSAIDs) with the exception of fenoprofen have been imprinted and their MIPs were applied in the form of MISPE from environmental samples [29]. This is expected as NSAIDs are classified as the most consumed pharmaceuticals by humans with antipyretic activities in some countries such as South Africa [64]. The emerging environmental pollutants such as antiretroviral drugs (ARVs) are imprinted [63, 65], however, there is still limited/no information on their environmental extraction using MISPE. Most MISPE applications for ARVs are based on their extraction from biological samples [66, 67]. The application of MISPE allows for pre-concentration of various analytes from environmental samples which in turn lead to very low detection limits in μg.L−1 to ng.L−1 levels (**Table 4**). Based on higher extraction efficiency or percent recoveries for pharmaceuticals, MIPs show strong ability to extract such drugs from complex sample matrices such as wastewater. As can be seen in **Table 4**, various amounts of MIPs are used in SPE. Small quantities as demonstrated by Zunngu et al. [3] are the significant of potential application in miniaturization techniques.

#### **6.2. Chromatographic analysis**

One of the most important applications of MIPs is their usage as the chromatographic stationary phases. This is done by slurry packing the prepared MIP into the stainless still chromatographic column. During the application, the imprinted molecule binds strongly to the packing material, which results in its strong retention and longer retention time [56]. This application was demonstrated in literature where a chiral stationary phase for the enantioselective separation of naproxen was reported [56]. In their work [56], a MIP was synthesized using (*S*)-naproxen as the template and evaluated for chromatographic separation. Racemic naproxen was efficiently resolved on the MIP with (*S*)-naproxen eluted last. Similarly, Haginaka and Sanbe, [70], synthesized a uniformly sized MIP for (*S*)-naproxen that gave good enantioselectivity and resolution for naproxen. In addition, uniform-sized MIP material for (*S*)-propranolol when applied as chromatographic stationary phase has shown the ability to separate (*S*)-propranolol from a mixture that contains some structurally related β-adrenergic antagonists [71]. Due to the strong binding of target compound onto MIP, peak tailing on the chromatogram is usually evident. Therefore, there are opportunities relating to the improvement of the quality of the resulting chromatograms.


**Table 4.** MISPE of pharmaceuticals from environmental waters.
