# Doped Zinc Oxide Nanoparticles: Synthesis, Characterization and Potential Use in Nanomedicine
## 3 Synthesis Methods and Characterization
### Wet Chemical Methods  
Wet chemical methods are among the most promising techniques adopted to synthesize micro- and nanostructured materials. Among the main advantages are the use of non-toxic solvents, low synthesis temperatures, and the use of simple equipment. Moreover, due to the relatively good purity and resulting stoichiometry of the resulting material, wet chemical methods appear to be a promising choice for the development of doped ZnO nanoparticles. A typical sol-gel/hydrothermal method to prepare ZnO-based materials is based on the following reactions [69]:  
\[\mathrm{Zn^{2+}+2 OH^{-}\to Zn(OH)_{2}}, \tag{1}\]  
\[\mathrm{Zn(OH)_{2}+2 OH^{-}\to Zn(OH)^{2-}}, \tag{2}\]  
\[\mathrm{Zn(OH)^{2-}}_{4}\to ZnO+H_{2}O+2 OH^{-} \tag{3}\]  
Typically, this process is assisted by a mineralizing agent that provides the OH\({}^{-}\) groups necessary to tune the pH of the solution, avoiding the precipitation of zinc hydroxide and promoting the formation of ZnO. Typical choices are NaOH [145], KOH [69] and, less often, NH\({}_{4}\)OH [155]. Among the zinc precursors, the main used are zinc acetate [156,157], zinc nitrate [158,159] and zinc chloride [150,160,161], which readily dissolve in most of the solvents used in this kind of reaction (water [162, 152], ethanol [163] and methanol [164]). For the dopant precursor, chlorides [138], nitrates [165,166] and acetates [144] from the corresponding dopant elements are the typical choices. Figure 3: Possible morphologies of ZnO nanostructured systems. From left to right and from top to bottom: nanoflowers (adapted from ref. [149]), nanopods (adapted from ref. [147]), nanorods (adapted from ref. [148]), mesoporous films, spherical nanoparticles, nanoneedles (adapted from ref. [150]), hollow microcolumns (adapted from ref. [151]), and micropods (adapted from ref. [152]). Then, the inclusion of the dopant can be obtained in a practically straightforward way, by mixing the dopant ion solution together with the zinc precursor solution, before mixing with the base. Another challenging aspect is the design of particles with an appropriate morphology. Indeed, it play an important role in determining the NPs biological behavior, influencing factors such as cell internalization. The morphology and the dimension of the nanoparticles can be controlled through surfactants such as sodium dodecyl sulphate [167] or cetyltrimethylammonium bromide [168]. Moreover, the use of different surfactants in different amounts has been demonstrated to completely change the final morphology of the particles, leading to very peculiar shapes such as nanoflowers, nanomultiopods or even nanopyramids [169]. The sol-gel approach is widely used when doping ZnO with rare earth elements is pursued. [PERSON] et al. reported the synthesis of Gd-doped ZnO nanorods by means of a wet chemical solution route that involved zinc chloride and gadolinium (III) chloride hydrate dissolved in distilled water [161]. The salt solution was prepared to have Gd\({}^{3+}\) at a 5 mol.% concentration with respect to ZnO, and it was mixed dropwise to a sodium hydroxide (NaOH) solution in order to get powder precipitation. By TEM and XRD analyses, the authors found useful information about the structural changes occurring in the ZnO wurtzite crystalline structure: after the correct insertion of Gd dopant, there was no other secondary phase in the resulting material. An increase of the unit cell parameters for Gd-doped ZnO (\(a=3.2524\) A, \(c=5.2095\) A and V \(=47.73\) A\({}^{3}\)) was found with respect to the pure ZnO nanorods (\(a=3.2518\) A, \(c=5.2095\) A and V \(=47.70\) A\({}^{3}\)), as expected from the larger ionic radius of Gd\({}^{3+}\) (0.94 A), with replacement taking place at the Zn\({}^{2+}\) sites in the host ZnO lattice, which is able to modify the dimensions of the crystal unit cell. This distortion of the crystalline cell leads to an enhancement of the piezoelectric coefficient, which changed from 12.4 pm/V of pure ZnO [115] to 45.49 pm/V for the Gd-doped nanoparticles (maximum value).