# Sol-Gel Silica Nanoparticles in Medicine: A Natural Choice. Design, Synthesis and Products
## 3 Silica NP Design
### NPs Synthesis Methodologies
#### 3.3.3 Solution Route  
The _solution route_ is the most common sol-gel synthesis process. Here metallic salts, metal alkoxides, or other organometallic precursors undergo hydrolysis and condensation, to form a wide range of sol-gel products. The right choice of catalyst, pH, water to silica precursor's ratio (to control hydrolysis rate), type of solvent and solvent to water ratio (to enhance reactants mixing), type of silicon precursor (as R may have inductive and steric effects on hydrolysis rate), the presence of chelating agent (to control the relative hydrolysis to condensation rate) and finally the temperature, allow the control of SiO\({}_{2}\) structure, size and/or morphology (Figure 7). Due to the hydrophobic nature of the alkyl groups organometallic precursors and water are not miscible, and the addition of a common solvent (usually an alcohol) becomes mandatory to promote miscibility between reactants. In the case of silica synthesis, the low polarity of the Si-O bond in silicon alkoxide (the Si atom bear \(5^{+}\) = 0.32 low positive charge in TEOS) is responsible for the slow sol-gel progress, rendering catalysis essential. Sol-gel basic conditions confer negative surface charges to the silica monomers (pH >> pHPZC, and \(\zeta\leq-30\) mV), which (kinetically) stabilize the silica suspension, allowing the formation of NPs. Above pH 7, maximum NPs growth is achieved, as a consequence of the increase in silica solubility, which promotes depolymerization of siloxane bonds, and produces monomeric silica necessary for the aging process. As to NPs, [PERSON] developed a mild synthetic protocol (room temperature, pH -9-11) for growing (quasi)monodispersed spherical NPs (with diameters between 50 nm and 2 mm) based on sol-gel silicon alkoxides and sodium silicate solution (SSS) as seeds (Figure 8). An alkoxide precursor (such as TEOS) is hydrolyzed (in an ethanol solution) to produce siliciic acid, which then undergoes a condensation reaction to form amorphous silica NPs. [PERSON] and [PERSON] [133] obtained sub-200 nm NPs by slightly modifying the Stober method. On the other hand, synthesized SiO\({}_{2}\) NPs (in sub-100 nm size range) present high polydispersity and irregular shape. [PERSON] et al. [30] proposed a procedure to produce monodisperse spherical SiO\({}_{2}\) NPs with sizes ranging between 30-100 nm, based in the classical two-dimensional LaMer [134] model. The strategy is built upon an effective selection of reaction conditions for the Stober method, and relies on a modification of the conceptual classical LaMer model of nucleation and particle growth. The LaMer methodology, supported on the protocols by [PERSON] et al. [133] allow the synthesis of NPs at room temperature in less than 1 h.  
Figure 8: NPs sol-gel Stöber synthesis method. Figure 7: Sol-gel products diversity: the right choice of catalyst, pH value, water to silica precursor’s ratio, type of solvent and solvent to water ratio, type of silicon precursor, presence of chelating agent, and temperature, allow the control of SiO\({}_{2}\) topology. Generally acid conditions favor the production of gels, as the silica formed in acid solutions possesses little or no surface charge (zeta potential will be in the tricky range of \(\zeta<130\) eV, PZC silica \(\sim\)pH = 2.2) facilitating flocculation/connectivity between silica species. Here the hydrolysis step is typically the fastest, but condensation begins before hydrolysis is complete. Condensation often occurs in terminal silanols, resulting in chain like structures in the sol and network-like gels. Linear or highly branched polymeric species are formed, given rise to 3D structures. To synthetize SiO\({}_{2}\) NPs under acid-catalyzed process a reverse-micelle (or water-in-oil microemulsion) system is formed by adding water, oil and surfactant. The hydrolysis and condensation reactions will develop in the confined reaction vessels (formed by the dispersed aqueous phase in the continuous oil matrix (Figure 9)).