## 3 Results and Discussion
### In Vitro Drug Release and Mathematical Modeling  
From the developed formulations shown in Table 1, the formulation XBM-Ca-F9 presented the highest EE% and, therefore, was used as a model in the study of drug release. According to Figure 8, approximately half of the initial loading of 5-ASA was released into the dissolution medium in approximately 4 h. In fact, despite the initial release, the amount released after 12 h of the experiment reached 60%. This result indicates that the formulation XBM-Ca-F9 might be able to reach the large intestine with approximately 40% of its initial loading in 5-ASA, which was later confirmed (36.4% \(\pm\) 1.1%) by the extraction of the 5-ASA from the matrix after 12 h.  
This initial release observed in the beginning of the experiment may happen due to the hydration and relaxation of the xylan chains that allow the drug diffusion [29]. However, the ability to hold 40% of its initial load after 4 h might be enough for the local treatment of the inflammation. In fact, previous studies with successful pharmacological response carried out with microgranules containing 5-ASA (Pentasa(r)) showed that the delivery systems reached the colon region in approximately 4 to 6 h [30]. The retention of the 5-ASA for such a long period into the XBM-Ca-F9 matrix leads to the hypothesis of the ability to deliver the 5-ASA in the colon region by the XBM-Ca-F9 formulation, since it was for  
Figure 7: X-ray diffractograms of pure 5-ASA (IV), Formulation XBM-Ca-F9 without drug (III), xylan (II), and Formulation XBM-Ca-F9 loaded with 5-ASA (I).  
xplan conjugates with 5-fluorouracil ([PERSON] and co-workers (2017)). In this work, the authors performed a dissolution assay using the materials and fluids from rats' gastrointestinal tract [31].  
In order to understand the mechanism on the initial release of 5-ASA from XBM-Ca-F9, some mathematical models were applied to the data. Initially, a first attempt was made to fit the data to a concentration independent model (e.g., linear model). However, the drug was not released in a constant rate. Thus, models that considered a non-linear release were tested. The Higuchi, Korsmeyer-Peppas, and Peppas-Shalin models were, then, tried. The Higuchi model showed a poor adjustment to the data, likely due to the non Fickian diffusion of the drug through the polymeric matrix, which will be later discussed. On the other hand, the Korsmeyer-Peppas and the Peppas-Shalin model, which consider the Fickian diffusion and the relaxation of the polymeric chains, were able to best fit the data. Therefore, the Peppas-Shalin model with t-lag was the one with best fitting parameters, once it considers a lag time for the beginning of the drug release (See Table S1) [29; 32]. Thus, according to the predictive model, the main mechanism of the 5-ASA release from the Formulation XBM-Ca-F9 was the relaxation of the xylan chains. In addition, it was seen that the contribution of the Fickian diffusion decreased, while the contribution of the relaxation increased over the time.  
The release profile observed for the XBM-Ca-F9 was quite different from the xylan-based particles previously produced by our group. The crosslinked microcapsules prepared by [PERSON] et al. (2013) kept constantly the release of the drug into the buffer media, while the spray-dried formulations completely release the drug once in contact to the medium [9]. Thus, to the best of our knowledge, the xylan-based particles developed had the highest encapsulation efficiency and the best drug release profile for physical encapsulation of 5-ASA.