# Journey to the Market: The Evolution of Biodegradable Drug Delivery Systems
## 2 The Evolution of Biodegradable Polymeric Drug Delivery Systems
### Emulsion Method  
Solvent emulsion extraction/evaporation is one of the most common methods used to produce polymeric microspheric particles [213] and it is widely used due to advantages in terms of simplicity, non-temperature sensitive, and good performance in particle size control [212]. Since reports of the first generation of oil-in-water (_o/w_) methods decades ago, there have been a large number of improvements aimed at encapsulating substances with a diverse range of physicochemical properties (e.g., hydrophobic, hydrophilic, large/small molecular weight). Generally, a single emulsion (_o/w_) can be applied to hydrophobic drugs while double emulsions (_w/o/w_) can be applied to hydrophilic drugs. In brief, for the single emulsion method, the drug for encapsulation is dissolved in the solvent phase to which is added the anti-solvent phase with stirring and homogenisation to form the polymeric microspheric particles loaded with drug [214; 215]. For most hydrophobic drugs, the procedures usually comprise three steps: (a) the polymer is dispersed and emulsified into an aqueous phase with emulsifier; (b) the solvent of the emulsion droplets is diffused into the aqueous phase; and (c) the solvent is removed by evaporation and the particles are solidified in the aqueous phase [216]. The type and concentration of emulsifier added into the aqueous phase and/or organic solution, plays a crucial role in determining the polymeric formulation properties in terms of quality, actual drug loading, encapsulation efficiency, drug release, pharmacokinetics, and cellular uptake/interaction, etc. [217; 218; 219]. The typical surfactants (stabilizers) commonly used are poly(vinyl alcohol) (PVA), PEG, PEG-lipid, proteins, and carbohydrates [220; 221; 222]. Furthermore, the stirring speed and evaporation time of the organic solvent used has a significant impact on the size distribution of the particles formed [223], which potentially can affect product injection ability (for parenteral formulations), biodistribution, side-effects, and the release profile of the encapsulated drug [224; 225].  
In some cases, the drug candidates are hydrophilic and/or are in the form of water-soluble salts. Hence, a water-in-oil-in-water method (_w1/o1/w2_) can be used to encapsulate hydrophilic drugs within biopolymeric particles. Unfortunately, in most cases, the encapsulation efficiency (EE) is poor for hydrophilic small molecules at approximately 20-30% [226; 227]. To address this issue, non-ionic surfactants may be added [222] or the hydrophilic salt form of the drugs of interest can be converted to the corresponding free base forms for weakly basic drugs or to the free acid forms for weakly acidic drugs [228], with the EE increasing to 90% and 56%, respectively. Another variant of the emulsion method is the water-in oil-in-oil method (_w1/o1/o2_) where the w2 water phase is replaced by an organic solvent that is immiscible with the first organic phase and acts as an anti-solvent to the polymer and the drug [229]. For the drug of interest (e.g., methotrexate), the EE was moderately increased from 44% to 51%, but a major drawback was the large amount of the o2 phase used, such as paraffin, which brings in problems such as solvent residues in the microspheres and problems in recycling and un-friendly environmental issues [229].