**3.3 Polymeric nanoparticle stabilization**

Stabilizing the produced nanoparticles is a key factor in the delivery systems because the nanoparticles need to protect the encapsulated drugs from degradation. Agglomeration and flocculation are the destruction methods of nanoparticles and can produce macroscopic lumps that lead to the diffusion of drug molecules and their degradation in the residence environment. To stabilize these nanoparticles, an emulsion stabilizer is required, and this can be efficiently accomplished with amphiphilic molecules. These molecules contain two components, a hydrophilic part, and a lipophilic side. Typical examples of amphiphilic molecules include Span 80 and Tween 80 as nonionic emulsifiers. Additionally, anionic emulsifiers, cationic emulsifiers, and zwitterionic emulsifiers provide structural diversity.

The most commonly used rule for emulsifier selection is the hydrophiliclipophilic balance (HLB) scale (HLB scale ranges from 0 to 20). This scale indicates the relative fraction of hydrophilic to lipophilic parts within the emulsifier molecule. High HLB values (8.0–18.0) are more suitable for use in O/W emulsions because they have a higher degree of hydrophilicity. In this case, O/W emulsions with a large amount of water are required to allow the formation of polymer dispersion droplets. As a result, these emulsifiers can widely expand the applications of the hydrophilic molecule for nanoparticle isolation, which then leads to interrupted agglomeration. Emulsifiers that have HLB values between 3.5 and 6.0 are most commonly used in W/O emulsions because they are more lipophilic [28, 29]. **Figure 4c** illustrates the expansion of the hydrophilic molecules of Span 80 (HLB = 4.3) and Tween 80 (HLB = 15.0) [7] at the interface of dispersed polymer droplets.

Furthermore, polymers have been used as emulsion stabilizers during emulsifier preparation methods, i.e., PVA, chitosan, and alginate [22, 30]. High MW polymers (>10 kDa) show driving forces that are equivalent to or greater than van der Waals-London (VDWL) forces. These VDWL forces are the primary source of attraction between nanoparticle surfaces and cause them to clump together. Through the addition of polymers, the polymeric chains can stabilize the nanoparticles via electrostatic, steric, and depletion forces. Electrostatic stabilization can be applied to charged polymers based on the simple principle that similar electric charges repel each other. Nanoparticle surfaces with zeta potential values greater than +30 mV or less than −30 mV are normally considered stable, as presented in **Figure 5a**. Steric stabilization is achieved on the surfaces of nanoparticles via adsorbed or chemically attached nonionic/ionic polymers. These uncharged polymers have a steric barrier due to a long chain that prevents the nanoparticles from sticking together (**Figure 5b**). Moreover, the addition of a high concentration of polymer for stabilization could lead to a high amount of free polymer in the dispersion medium. These free polymers establish repulsive forces between the nanoparticles to prevent nanoparticle aggregation and act as depletion stabilizers (**Figure 5c**) [31].

For example, PVA is an uncharged polymer that is commonly used as an emulsion stabilizer for the preparation of PLGA nanoparticles. The hydroxyl groups on the PVA chains are adsorbed at the interface with the PLGA chains via the hydroxyl, carboxylic acid, and ester groups. The interface between PLGA and PVA is an area with strong interactions, resulting in high nanoparticle stabilization [32, 33]. This interaction corresponds to the molecular orientation of PLGA nanospheres and PLGA nanocapsules (**Figure 4**). **Figure 5d** proposes a schematic representation of the molecular orientation of PVA at the surface of PLGA nanoparticles.

The use of polymers as stabilizers affects the characteristics of the nanoparticles to a greater extent than the use of other emulsifiers; as a result, these nanoparticles have a high MW. As a result, the use of low MW polymers or polymers at a low concentration results in reduced stability, lower drug loading, a rapid release rate, and a smaller size compared with high MW polymers or polymers present in high concentrations [6]. In addition, the charged polymers affect aliphatic polyester

#### **Figure 5.**

*Schematic representation of the molecular interactions of electrostatic stabilization (a), steric stabilization (b), depletion stabilization (c), and PVA at the surface of PLGA nanoparticles (d), based on information from a review article [31–33].*

nanoparticles. Alginate is an anionic polymer and contains carboxylate anions (▬COO<sup>−</sup> ) on its polymer chains. These anions repel the anions of the aliphatic polyesters, resulting in a larger size and permitting an increase in the retention of cationic drugs. However, cationic polymers (i.e., chitosan with a ▬NH3 + groups) interact with the carboxylate anions of the stabilizing polymers, leading to reduced particle size and increased retention of anionic drugs [30].
