## 3 Results and Discussion
### BTA Release Studies from Carboxymethyl Cellulose Microspheres
#### 3.5.2 Release Studies
[41] reported the encapsulation of different natural antioxidants in sodium carboxymethyl cellulose, with releases of 50% of the encapsulated material in the first 10 min, as well as total releases at 45 min, 2 h and 4 h. The encapsulation of soybean extracts in sodium carboxymethyl cellulose by [PERSON] et al. [42] showed that the prepared microparticles were readily soluble in water, and released 80-100% of the encapsulated material in 15-30 min. Furthermore, [PERSON] et al. [40] studied the encapsulation of piroxicam in CMC-Na, and observed a 50% release of the drug (at pH 7.4) from the polymeric matrix within 20 min. [PERSON] et al. [53] reported the encapsulation of a poorly water-soluble drug, ibuprofen, in a gelatin matrix as a water-soluble polymer shell. Briefly, in a spray drying process of gelatin dissolved in ethanol-water mixtures, the evaporation of both ethanol and water first takes place, simultaneously, at the surface of the droplet. As the atomized liquid droplets contact the drying air, a concentration of solute at the surface occurs which leads to the formation of a layer (crust) of gelatin on the surface of droplets [46; 53; 54; 55]. This layer will act as a semi-permeable membrane that allows the continuous evaporation of water, but should retain ethanol [54; 55]. Due to the similar characteristics, it is possible to draw a parallel between the literature and our results, though these studies [53] have been performed for lower inlet temperatures. Nonetheless, in order to understand BTA's release behavior from the CMC microspheres, the glass-transition temperature of the polymeric wall material (CMC:PVA) should also be taken into consideration. The glass-transition temperature (T\({}_{g}\)) controls the diffusion of the encapsulated material (BTA) through the barrier formed by the wall material (CMC:PVA), which depends on whether the wall material retains its glassy state during spray drying [35]. Below the glass transition of CMC:PVA, the diffusion of BTA through the polymeric wall material would be limited, since the polymers are in their glassy state, however if spray drying occurs above the glass-transition temperature, the polymeric wall would be in a rubbery state, which would promote a faster diffusion of BTA. This will not only influence the product yield (as it was mentioned before) but suggests an influence on drug release due to the matrix-type nature of CMC-Na microspheres, where a small fraction of the encapsulated material remains exposed on the microparticles' surface [18; 53]. For conditions 5 and 6, CMC.BTA microspheres were prepared at 190 \({}^{\circ}\)C, a temperature well above the glass-transition temperature reported in the literature for CMC:PVA mixtures (75-80 \({}^{\circ}\)C) [45; 50], which means that, upon drying the microspheres, formation was characterized by a high rubbery state. Therefore, these conditions may lead to a faster diffusion of BTA towards the microspheres' surface. The result of this process can be a rapid formation of the microspheres with more BTA located near/at the surface of the polymeric microspheres, which might explain the higher extent of BTA release for short times. Understanding the release process, from microparticles is of utmost importance to improve microparticulate formulations for controlled release purposes. A first approach to the assessment of release mechanisms is fitting experimental data to the Korsmeyer-Peppas equation [43]. However, since this equation can only be applied to the first 60% of release, due to the high release observed, it is not possible to fit the experimental data to this semi empirical equation [43]. On the other hand, the loading capacity allows us to assess whether the amount of BTA released is hindered due to its poor solubility in water or by another mechanism. According to Sigma-Aldrich's safety data sheet [56], Benzotriazole's solubility in water is 19 g/L. Considering that in the release studies, 50 mL of water were used, the maximum amount of BTA subject to solubilization in water would be 0.95 g/L.