6.3.4.1　Emulsion-solvent evaporation method

Typically，the hydrophobic polymers and drugs are firstly dissolved in a waterimmiscible and low boiling point organic solvent as the oil phase，then emulsified by an aqueous phase containing surfactants to form an oil-in-water（O/W）emulsion，followed by evaporation of the organic solvent to form a nano-drug delivery system（Figure 6-4）.Organic solvents of the oil phase should be more volatile than water，such as dichloromethane，chloroform，toluene and ethyl acetate.Among them，the toxicity of ethyl acetate is very low.The distribution of drug molecules in the carriers depends on the hydrophobicity and the strength of interaction between them.If the interaction between drugs and carriers is very weak，the drugs with weak hydrophobicity tend to be distributed near the surface of the carriers.On the contrary，the drugs with strong hydrophobicity are distributed inside the carriers.Reversed-phase（W/O）emulsions can be applied to load hydrophilic drugs in hydrophilic polymer carriers，in which both the polymers and the drugs are firstly dissolved in water and the surfactant is dissolved in the oil phase.Reversed-phase emulsions require that the organic solvent is harder to evaporate than water.

The advantages of emulsion-solvent evaporation method are high encapsulation efficiency，precise control of drug loading，and this method is capable to load multiple drugs or testing reagents simultaneously.Hydrophobic biodegradable polymers such as PLA and PLGA can be used to prepare nano-drug carriers by this method.The size of the nano-drug carriers can be easily controlled by varying the size of the emulsion droplets and the concentration of the polymers.The size uniformity depends on the emulsification method，which is generally inferior to the spherical micelles，but better than NPs obtained by the selforganized nano-precipitation method.Majority surfactants in the products can be removed by centrifugation or dialysis，but few residuals are inevitable.To reduce the toxic and side effects of surfactants，nonionic surfactants such as poly（vinyl alcohol）（PVA）can be used.(https://www.daowen.com)

Based on emulsion-solvent evaporation method，researchers also developed the double emulsion-solvent evaporation method，which can be used to prepare nano-capsules.Double emulsions are complex emulsions formed through further secondary emulsification of ordinary emulsion，which are also known as multilayer emulsions.If water-in-oil（W/O）single emulsion is secondary emulsified in water phase，W/O/W multiple emulsion will be achieved.On the contrary，O/W/O multiple emulsion is able to be obtained via secondary emulsification of O/W single emulsion in oil phase.The double emulsions contain internal phase，intermediate phase and external phase.W/O/W multiple emulsion has been applied for nano-drug carriers.Water-soluble drugs are dissolved in internal phase and oil-soluble polymers are dissolved in the intermediate phase.Nano-capsules can be obtained after complete evaporation of the organic solvent.At the same time，oil-soluble drugs can also be added in the intermediate phase.The size of the double emulsions is generally greater than single emulsions，while the uniformity is inferior to single emulsions.The size of capsules is usually hundreds of nanometers in size.Apart from secondary emulsification，phase separation also can be introduced to generate double emulsions.For example，a non-volatile poor solvent（O'）can be added in the oil phase of the emulsion.With the evaporation of the organic solvent of the oil phase，phase separation between O'and polymer occurs，resulting in O/O/W multiple emulsion.For instant，cooking oil can be served as the non-volatile poor solvent.However，by adding absorbent materials（such as sodium dioctyl sulfosuccinate）in the oil phase of O/W emulsion droplets，W/O/W multiple emulsion can be achieved.Specifically，the water molecules diffuse into the droplets and form the internal phase，which can be used to load water-soluble drugs.Both size and uniformity of the droplets could be improved by employing the phase strategy（see extended reading 2）.