# Green Strategies for Molecularly Imprinted Polymer Development
## Green Strategies in MIP Development
### Ultrasound-Assisted MIP Synthesis  
Ultrasound-assisted polymer synthesis has been extensively used to enhance the reaction rate [80], taking advantage of the formation and collapse of small bubbles by the cavitation caused by ultrasonic energy, which increases the solubility of template and monomers, diffusivity, penetration, and transportation of species in the medium [81; 82]. This technology brings several advantages in MIP synthesis when compared with traditional polymerization processes, because it promotes higher reaction rates, more homogeneous polymer chain growth, higher yields, and milder conditions (e.g., low reaction temperature) [83; 84]. Furthermore, it can alter the binding site population distribution, and thus, the morphology of the final polymer [82]. Only a few works have reported on MIP synthesis by ultrasound-assisted polymerization. However, MIPs prepared ultrasonically presented binding properties similar or superior to the conventional methods [82; 84; 85]. The first MIP produced using ultrasound-assisted polymerization was reported in 2006 by [PERSON] [82], in which theophylline (THO)-imprinted polymers were produced using MAA, EGDMA, and AIBN as functional monomer, crosslinker, and free radical initiator, respectively, for chromatographic processes. THO is a drug extensively used in the treatment of asthma, even though its use has continually declined over the years, due to its side effects and toxicity [86]. Polymerization reactions were performed at 65 \({}^{\circ}\)C for 4 h using an ultrasonic bath operating at 35 kHz. Polymers were obtained similarly to conventional MIP protocols. A white monolith was obtained that was further crushed, ground, and sieved through a 63 \(\upmu\)m sieve. Polymer was obtained as irregular particles with 60-65% yield. Moreover, the cavitation showed had no influence on polymers produced, however, less time was required for polymerization process and the binding characteristics of polymers obtained could be compared with MIPs prepared using more traditional protocols. The encapsulation of magnetic nanoparticles by 17$-estradiol-imprinted polymers using ultrasonication-assisted synthesis was reported by [PERSON] et al. [87] for fast removal of 17$-estradiol from aqueous environments. In this case, MAA was used as monomer, EGDMA as crosslinker, and AIBN as initiator, at 42 kHz, 65 \({}^{\circ}\)C for 2 h. The average particle size diameters of magnetic NIPs and magnetic MIPs were 200 and 300 nm, respectively. The use of ultrasound not only enhanced the polymerization rate and morphology of the nanoparticles, but also led to an increase in the number of free radicals, and thus, facilitated MIP growth around the magnetic nanoparticles. The adsorption capacity towards to 17$-estradiol was comparable to traditional approaches. Ultrasound-assisted precipitation polymerization was also used in the production of caffeine-MIP supported on magnetic particles by [PERSON] et al. [88]. In this example, the affinity layer was produced using MAA as monomer, EGDMA as crosslinker, and BPO as initiator. Polymerization reactions were performed using an ultrasonic bath operating at 37 kHz, and kept at 60 \({}^{\circ}\)C between 0.5 to 4 h. Copolymers were obtained as agglomerates of particles with similar size. The yields of magnetic MIPs increased from 0.5 to 4 h (47.1-62.4%). Moreover, binding properties were evaluated in static mode for 16 h where magnetic MIPs produced ultrasonically for 4 h obtained the best result, adsorbing 11.14 times more than the magnetic NIPs. Affinity properties were also evaluated using THO as analogue molecule, and particles were shown to be very selective. The reusability of structures was finally assessed, and the adsorption amounts of caffeine were kept almost constant for five cycles.