*3.3. Surfactant-Coated Co-Crystals*

Nano co-crystals were initially synthesized without the use of surfactants and then with surfactants to identify the effect of surfactant addition on crystal production. Generally, the use of surfactants yielded co-crystals in the nanometer size range. The trend observed shows optimal stabilization was achieved when electrostatic stabilization is prevalent. Non-ionic surfactants with high hydrophilic-lipophilic balance (HLB) values exhibited low steric stabilization concentrations due to the presence of relatively large hydrophilic heads in the surfactant. PS, PDI and ZP data for surfactant free NCC have been added to Table 3 for comparative purposes. The data reported for PS is intensity distribution and z-average.


**Table 3.** Summary of results from general factorial experiments.

### 3.3.1. Particle Size (PS) and Polydispersity Index (PDI)

The resultant particle size and PDI of the NCC was smaller when surfactant was used during the sonication phase of the production process. The interaction plots of PS and PDI using different surfactants and concentrations are depicted in Figures 5 and 6.

**Figure 5.** PS of nano co-crystals using different surfactants at concentrations of 0.5% *w*/*v* (red), 1% *w*/*v* (green) and 2% *w*/*v* (blue).

The reduction in particle size observed was greatest when SDS was used, due the electrostatic stabilization achieved with this stabilizer. At lower concentrations, higher molecular weight surfactants exhibited sufficient steric stabilization. For instance, Tween® 80 exhibited sufficient steric stabilization to produce crystals with a desirable PS and PDI, which can be attributed to the presence of a long hydrophobic chain and a considerably large hydrophilic head. It results in a reduction in PS and a low PDI indicating a narrow particle size distribution was achieved. The result is that fewer molecules of the surfactant are required to shield nucleating nano co-crystals from the balance of the materials in solution [25,59]. As the concentration of Tween® 80 increased, the PDI and PS of the nano co-crystals increased, and this was attributed to agglomeration behavior of the crystals. Of the non-ionic surfactants used, TPGS 1000 produced crystals with the smallest size at intermediate

concentrations with a PDI < 0.500 at all concentrations tested. The larger polyethylene glycol molecules have more polar heads and result in stabilization at lower concentrations due to a larger shielding effect while also forming a monolayer around crystals. The nano co-crystals stabilized using Span® 80 exhibited a desirable PS and PDI as the concentration approached 2% *<sup>w</sup>*/*<sup>v</sup>*. Due to the presence of a smaller hydrophilic head, Span® 80 requires a much larger concentration to achieve the same CQA when compared to TPGS 1000 and Tween® 80. However, below the critical micelle concentration, ionic surfactants are better stabilizers than non-ionic compounds since ionic surfactants impart a surface charge to crystals, which results in electrical repulsion and better stabilization [60], as was evidenced for NCC stabilized using SDS.

**Figure 6.** PDI of nano co-crystals using different surfactants at concentrations of 0.5% *w*/*v* (red), 1% *w*/*v* (green) and 2% *w*/*v* (blue).

The general trend depicted by the interaction plot for PDI in Figure 6 shows that an increase in concentration results in a lower PDI. As the concentration of each surfactant approached 2% *w*/*v* (blue line) the PDI values were lowest. This is attributable to the larg amount of available surfactant to prevent growth at the surface of several nuclei in solution resulting in a more uniform distribution of particle sizes. In addition to affecting the steric layer thickness, molecular weight and chain length; viscosity is also affected [60]. The higher the molecular weight, the higher the viscosity. In the final product, high viscosity can enhance the stability against aggregation [61]. This suggests that the molecular weight of the surfactants not only reduces particle or crystal size and PDI, but could potentially enhance stability.
