# Precipitation Polymerization: A Powerful Tool for Preparation of Uniform Polymer Particles
## 2 Categories of Precipitation Polymerization
### Distillation/_Reflux_ Precipitation Polymerization_  
Distillation precipitation polymerization (DPP) is a method of controlling microsphere formation by solvent distillation during the polymerization process. The solvent will evaporate out with the increase in the temperature, and the concentration of the reactants gradually increases, which would result in faster reaction rates [45]. [PERSON] and [PERSON] et al. have made efforts to achieve the hydrophilic property of the surface of the microspheres with wider ranges of polarity and functionality [29], as well as giving the growth mechanism for leading to good spherical shape [46; 47]. During the investigation of the hydrophilic poly(methacrylic acid) (PMAA) polymer particles, they proposed that the presence of hydrogen bonding interactions between the carboxylic acid groups as a non-covalent linkage or physical crosslinking plays a key role in the nucleation process [48]. Functional monomers such as methylates, acrylates, chloromethylstyrene, amide, pyrrolidone, carboxylic acid, and acrylonitrile were introduced to prepare narrow-disperse microspheres [49; 50; 51; 52; 53; 54]; meanwhile, the tri- or tetra-layer polymer and inorganic/polymer composite/hybrid microspheres with movable inner core have also achieved successfully [55; 56]. [PERSON] et al. then proposed a more efficient approach, reflux precipitation polymerization (RPP) [31], by simplifying the apparatus to a handy manual refluxing operation and introducing mechanical stirring, in which the well-defined polymeric nanogels could precipitate from the poor solvent without adhesion to the reaction flask inner wall that makes it easily be scaled up and freely time-controlled [30]. Currently, most of the efforts have focused on the combination of DPP or RPP with other polymerization techniques (e.g., living radical polymerization [57; 58] or 'click' chemistry [59; 60; 61]) to meet the use of specific materials in various areas, such as drug/gene delivery, glycopeptides/protein enrichment [62; 63], molecular recognition [45] and cell detection. For the precisely controlled structures, modular functionalities, and desirable payload encapsulation [49; 64; 65; 66; 67; 68], we can foresee its huge potential in preparing novel multifunctional nanostructures to meet the requirements of multidisciplinary applications [69]. In particular, a series of biodegradable zwitterionic stimuli-responsive (e.g., pH/redox) nanogels with crosslinker that contains disulfide bond or metal ions, especially for drug de  
Figure 3: Advantages of different precipitation polymerization techniques in preparation of polymer microspheres [29; 30; 31; 32; 33; 34; 35; 36; 37; 38; 39]. livery, via either DPP/RPP or aqueous precipitation polymerization, have been prepared for its advantages of avoiding the application of toxic surfactants and stabilizers [64; 65; 66; 67; 68; 69; 70; 71; 72; 73; 74; 75; 76]. Much of the residual functional groups on the core surface, which enables the polymer nanoparticles for further modification, remained [77; 78]. The applications in recognizing small organic molecules, especially for MIPs [79; 80], or facilitating the uniform polymer coating on the magnetic nanoparticle surface [81], have also attracted much attention. [PERSON] et al. combined RAFT and RPP for the synthesis of novel water-compatible MIPs with improved mass transport [57]. [PERSON] et al. prepared a novel kind of Ni\({}^{2+}\) immobilized crosslinked PMAA layer coated Fe\({}_{3}\)O\({}_{4}\) magnetic core, which was promising for practical applications of His-protein separation and purification in proteomics [82]. [PERSON] et al. developed superparamagnetic microspheres bearing phosphine oxide groups for effective extraction of uranium from highly acidic solution [83; 84]. [PERSON] et al. prepared Fe(II)-based coordination polymer nanohydrogels as a new type of nanozyme by RPP with \(N\),\(N^{\prime}\)-methylenebis(acrylamide) (MBA\({}_{\rm m}\)) as a crosslinker, showing a regular spherical morphology with a larger size (Figure 4) [76].