# Green Strategies for Molecularly Imprinted Polymer Development
## Green Strategies in MIP Development
### Supercritical Fluid Technology
The molecular imprinting method relies on the crosslinking of the growing polymer \"freezing\" the structure around the template molecules. The synthesis of a highly crosslinked polymer in scCO\({}_{2}\) was reported for the first time in 1999, by [PERSON] et al. [21] in which non-porous poly(divinylbenzene) microspheres were obtained by heterogeneous polymerization with a final average particle size diameter between 1 and 5 \(\upmu\)m.  
The first MIP produced under scCO\({}_{2}\) was reported by [PERSON] et al. [22] in 2006 for drug delivery purposes. Molecularly imprinted poly(diethylene glycol dimethacrylate) (polyDEGDMA) was produced by free radical polymerization (FRP) in scCO\({}_{2}\) using a carboxylic acid end-capped perfluoropolyether oil as stabilizer for two different template molecules, salicylic acid and acetylsalicylic acid, in different concentrations. An impregnation step was further performed, and the controlled released of the systems were evaluated. Discrete spherical polymer particles with 1.7 \(\upmu\)m diameter were obtained, and a correlation between the quantity of template used in MIP synthesis and the percentage of impregnation was achieved. In the same year, [PERSON] et al. [23] shared with the scientific community the preparation of MIP nanoparticles via non-covalent imprinting strategy, using methacrylic acid (MAA) as monomer, divinylbenzene (DVB) as crosslinker, and propranolol as template molecule by heterogeneous polymerization, obtaining discrete crosslinked polymer particles with an average particle size around 100 nm. Table 1 summarizes MIPs developed in scCO\({}_{2}\) for several applications. Boc-l-tryptophan-MIP was synthesized by free radical polymerization in scCO\({}_{2}\) for chiral separation [24]. Poly(ethylene glycol dimethacrylate) and poly(\(N\)-isopropylamide-\(co\)-ethylene glycol dimethacrylate) based MIPs were obtained as micron-sized particles, in high yields (\(\sim\)99%, determined gravimetrically) and ready to be slurry packed into HPLC blank column. Materials were evaluated as stationary phases for the enantiomeric separation of l- and d-tryptophan, and the polymeric materials were shown to be suitable for chiral separation for example in moving bed chromatography. A MIP with affinity for flufenamic acid (FA) was developed for controlled drug release, by FRP using MAA and \(N\)-isopropyl acrylamide (NIPAAm) as monomers, and ethylene glycol dimethacrylate (EGDMA) as crosslinker [25]. The effect of crosslinking degree and template/monomer ratio were evaluated. Poly(MAA-\(co\)-EGDMA) and P(NIPAAm-\(co\)-EGDMA) were obtained as micron-sized agglomerates of nano-primary smooth surfaced particles, in high yields and as dry powders. Further, scCO\({}_{2}\)-assisted impregnation of FA showed that the imprinted matrices were able to uptake higher amounts of FA, 101.5 mg drug.g\({}^{-1}\) polymer, compared to control non-imprinted polymer (NIP), 50.5 mg drug.g\({}^{-1}\) polymer. In another work, ibuprofen (IBU)-imprinted polymer was synthetized in which EGDMA was used as crosslinker and 2-(dimethylamino)ethyl methacrylate (DMAEMA) was used as functional monomer with pH-sensitive character [26]. A lower crosslinking degree polymeric matrix (20.2 wt %) compared to the typical 80-90%, was used in a mimicked real scenario at two different pHs. MIPs were obtained as agglomerates of well-defined particles with particle size approximately of 1 \(\upmu\)m, in high yields (\(\sim\)85%, determined gravimetrically) as dry and free-flowing powders. MIP showed a higher molecular recognition towards the template, 33.1 wt % of IBU, compared to 10.2 wt % for the NIP polymer. In the last years, bisphenol A (BPA) has been the focus of a widespread interest because of its presence and accumulation in the environment, especially in the water, but is found also in scaring levels in the amniotic liquid of pregnant women.