## 3 Results and Discussion
### Formulation Studies
#### 3.4.3 Drug Release and Permeability Assessment
Although the arrangement does not mimic active transport or enzymatic degradation processes of the intestinal epithelium, it offers a standardized method to evaluate drug diffusion post-digestion. The present study was used to compare the permeation potential of ACA and DIP after simulated gastrointestinal digestion. Notably, [PERSON] et al. [63] employed a similar approach, transferring digested samples from in vitro lipolysis to Franz cells to assess drug permeability, supporting the relevance of this method in evaluating post-digestion drug transport. As shown in Figure 7b and Table 6, dipyridamole exhibited limited permeation behavior (Papp = 0.1178 \(\pm\) 0.0121) due to its low solubility in alkaline conditions. In contrast, ACA + SAL (Papp = 0.3233 \(\pm\) 0.1219) rapidly achieved a high permeation level, indicating stable and efficient permeation across the membrane. (Figure 7b). The observed permeability profiles suggest that ACA may achieve faster, and more efficient absorption in vivo compared to DIP. This inference aligns with the Biopharmaceutics Classification System (BCS), where ACA is classified as a Class I compound (high solubility, high permeability) [40], and DIP falls under Class II (low solubility, high permeability [64]. The higher permeability of ACA observed in vitro correlates with its known rapid absorption and onset of action in clinical settings [65]. To bridge the in vitro findings with in vivo performance, it is essential to consider studies that have established in vitro-in vivo correlations (IVIVC). For instance, [PERSON] et al. [63] demonstrated a linear IVIVC for self-nanoemulsifying drug delivery systems (SNEDDS) by comparing the area under the curve (AUC) from in vitro permeation studies with in vivo plasma concentration profiles. Their findings underscore the potential of in vitro models, to predict in vivo pharmacokinetics for certain formulations. Based on our in vitro data and supported by the aforementioned studies, we anticipate that ACA will exhibit rapid absorption and onset of action in vivo, consistent with its clinical profile. DIP, while demonstrating moderate permeability in vitro, may benefit from formulation strategies aimed at enhancing its solubility and, consequently, its bioavailability. Nevertheless, we acknowledge that in vitro models cannot fully replicate the complexities of human physiology. Factors such as first-pass metabolism, enzymatic degradation and individual patient variability can influence the actual in vivo pharmacokinetics. Therefore, while our in vitro findings provide valuable insights, subsequent in vivo studies are necessary to validate these predictions and fully characterize the pharmacokinetic profiles of DIP and ACA. A particularly noteworthy observation in the overall release process (digestion and penetration stage) of the two active substances is related to the hydrolysis rate of ACA to SAL. According to the bar graph in Figure 8, while in the gastric phase, ACA is already hydrolyzed to a rate of \(>\)60%, this rate increases (\(>\)80%) in the intestinal tract. Then, during the study of the penetration rate of both substances, in Franz cells, approximately the same amounts of ACA and SAL were detected at the acceptor compartment (despite the low content of ACA in the intestinal tract). This leads to the conclusion that the permeation \begin{table}
\begin{tabular}{c c c c} \hline \hline
**APIs** & \begin{tabular}{c} **Jss (\(\mu\)g cm\({}^{-2}\)** \\ **min\({}^{-1}\))** \\ \end{tabular} & \
\begin{tabular}{c} **Papp (cm/min) \({}^{\star}\)** \\ **10\({}^{-2}\)** \\ \end{tabular} &
\begin{tabular}{c} **Statistical Significance** \\ **vs. DIP** \\ \end{tabular} \\ \hline DIP & 0.0769 \(\pm\) 0.0068 & 0.1178 \(\pm\) 0.0121 & - \\ ACA + SAL & 0.4778 \(\pm\) 0.1561 & 0.3233 \(\pm\) 0.1219 & Significant (\(p\) = 0.0439) \\ \hline \hline \end{tabular} \({}^{\star}\)Statistically significant difference at \(p\) \(<\) 0.05 (unpaired t-test, \(n\) = 3 per group).  
\end{table}