**5. Solvent based methods**

Solvent based methods have been proposed in order to encapsulate molecules with stability and bioavailability problems, despite toxicological issues of the solvent are a limiting aspect. One of the main advantages of solvent based methods is the mild operating temperature, which can be useful for the encapsulation of thermosensitive drugs. According to the different precursor/method used, solvent based methods can be divided in:


#### **5.1. Solvent injection method**

In solvent injection (or solvent displacement) method the lipid and the drug are dissolved in a water-miscible organic solvent (ethanol, acetone, isopropanol) and this solution is injected through a syringe needle in water under stirring: lipid precipitates as nanoparticles while contacting water, encapsulating the drug. Particle size can be influenced by lipid type, surfactant and solvent used, and from the viscosity of the outer phase [31,32].

#### **5.2. Solvent evaporation – Diffusion from emulsions**

SLN can also be prepared starting from emulsion precursor, whose organic phase is constituted by a solvent, which can be either volatile or partially water miscible.

O/W or W/O/W emulsions can be prepared: O/W emulsions are used for lipophilic drugs, that are dissolved in the inner organic phase of the system [33,34], together with the lipid. W/O/W emulsions are suitable for hydrophilic drugs, that are dissolved in the inner aqueous phase, while the lipid is dissolved in the intermediate organic phase of the multiple system [35,36].

Nanoparticles are formed when the solvent is removed either by evaporation (solvent evaporation technique for volatile solvents) [33, 35] or by water dilution (solvent diffusion technique for partially water miscible solvents) [34, 36]: owing to solvent removal lipid precipitates as nanoparticles encapsulating the drug.

Solvent evaporation technique is quite outdated and shows many drawbacks, due to the toxicity of chlorinated solvents used; solvent diffusion is more innovative and most of the solvent employed show a better safety profile compared to volatile solvents.
