**4. Synthesis of polymer composites**

pre-concentration and extraction of a certain group of compounds where a cocktail of pharmaceutical compounds is used in the polymerization set-up. Practical examples for this include the work of Duan et al. [26] where five acidic pharmaceuticals which are ibuprofen, naproxen, ketoprofen, diclofenac and clofibric acid, were used as multi-templates in a synthesized MIP that showed selective recognition and ability to extract these target compounds from lake water and WWTP effluent using molecularly imprinted solid-phase extraction (MISPE) technique. In their work, Duan et al. [26] obtained the recoveries that were greater than 95% for all five acidic pharmaceuticals in lake water and wastewater spiked with 1 μg.L−1 of each compound. Dai et al. [38] have also reported the selective removal of the same group of pharmaceutical compounds using a multitemplate MIP from contaminated water. These researchers demonstrated the selectivity of the multi-template MIP in the presence of fenoprofen and carbamazepine (both pharmaceutical compounds). In their study, the removal efficiency for the five target pharmaceuticals in water was greater than 80%, whereas, less than 40% was reported for fenoprofen and carbamazepine used as competitors. In the same aspect, a dual template (naproxen and ketoprofen) MIP has been reported [28], where the ability to recognize the template molecules was tested chromatographically in the presence of structural analogues (ibuprofen, fenbufen, fenoprofen and flurbiprofen). Also, Dai et al. [34] prepared a novel double-template MIP by precipitation polymerization using carbamazepine and

For a multi-template (naproxen, ibuprofen and diclofenac) MIP, it was observed that the selectivity collapses easily during the extraction of target compounds from aqueous phase [31]. This could be strongly influenced by bigger cavities that are created due to the usage of multi-templates. This could allow the easy access of many presumably smaller molecules into the binding sites. It has been demonstrated that the untargeted compounds can be selectively washed off from the multi-template MIP surface due to their weaker non-specific interactions with the polymer [31]. Contrarily, some researchers have indicated that the use of a dummy template during polymerization increased the selectivity of the final MIPs that target more

The usage of target compounds as template molecules could have negative impact on the analysis of real samples due to their bleeding upon application into the sample matrix. This could be severe in the cases of incomplete template removal. To avoid this problem, the use of dummy templates for the synthesis of MIPs has been proposed in many studies [41–43]. In certain instances, the selected dummy templates exhibit the properties of more than one compound, and its chemical structure is closely related or similar to more than one pharmaceutical drug [42, 44]. In such cases, the prepared MIP is able to selectively extract more than one compound. This has been demonstrated by the synthesis of a MIP using diphenylamine as the template whose chemical structure closely resembles that of both diclofenac and mefenamic acid (**Table 2**) [44]. As shown in **Table 2**, the dummy molecule (diphenylamine) for both diclofenac and mefenamic acid can be characterized by two

clofibric acid as the double templates.

that target one compound [39, 40].

**3.4. Dummy-templating**

56 Recent Research in Polymerization

Traditional imprinting produce particles with adsorption sites embedded deep into the polymer matrix resulting in difficulties with mass transfer of analyte molecules [45]. Dummy templating has been used to address the problem of elution of template molecules during MIP application in real world samples. This problem occurs due to incomplete template removal caused by molecules occupying deeper pores in the polymer matrix. However, as discussed earlier, the recognition sites created by the dummy might not perfectly fit the target analyte leading to inferior extraction efficiencies as when the template was used. Surface imprinting (polymer composite) has been proposed as an alternative to dummy templating for addressing the MIP template bleeding problem. Various materials including graphene oxide [46, 47], magnetic cross-linked chitosan [48, 49], silica [49, 50], carbon nanotubes [51], quantum dots [52] and nanoparticles [53, 54] have been used as scaffolds in the preparation of imprinted polymer composites for pharmaceutical compounds. The template is imprinted at or near the proximity of the surface, therefore, there are no deeper lying cavities that may cause slow release of template molecules and subsequently bleeding. The materials used as anchors usually have large surface area to volume ratio resulting in lower mass transfer resistance and faster rebinding due to accessibility of the binding site [47]. Cl-TiO<sup>2</sup> imprinted photo catalyst exhibited higher photo degradation rate (72%) of tetracycline under visible irradiation than non-imprinted photo catalyst [53]. Molecular imprinting magnetic γ-Fe2 O3 / 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 0.11 ng.mL−1 (S/N = 3), without any matrix effect, cross-reactivity and false-positives.
