## 3 Results and Discussion
### Formulation Studies
#### 3.4.3 Drug Release and Permeability Assessment  
Referring to the literature data, dipyridamole is a poorly water-soluble drug, and its degree of dissolution decreases with pH increase. It is absorbed better in the small  
Figure 6: Stability study of DIP (blue), ACA (red), SAL (green) in simulant fluid SGF, SIF and PBS at 37 \({}^{\circ}\)C, \(n=3\) and RSD < 1.5%. intestine [53]. On the other hand, aspirin, which is widely co-administered with dipyridamole [9], seems to be absorbed both in the intestinal epithelium (its ionized form) [54] and the stomach (non-ionized form) [55]. Of course, for its study, its significant rate of hydrolysis into salicylic acid (under alkaline conditions) should not be overlooked. Under the present circumstances, it was of interest to study the behavior of ACA and DIP in the gastrointestinal (GI) tract when incorporated into the chocolate/honey composition. Therefore, the proposed formulation was subjected to simulated gastrointestinal digestion using a standardized in vitro procedure [28]. For the study of the two active ingredients, the significant hydrolysis rate of ACA to salicylic acid (under alkaline conditions) also had to be taken seriously. Another point that should be clarified is that the in vitro standardized digestion model used in this study is based on adult gastrointestinal physiology. It is therefore important to recognize the limitations this imposes when predicting in vivo behavior in pediatric populations, due to physiological differences [56]. For example, children may exhibit slower gastric emptying times, lower enzyme activity, reduced bile salt concentration, and a different pH profile throughout the gastrointestinal tract [57; 58]. These factors can significantly affect the solubility, stability, and release kinetics of orally administered drugs. As a result, drug behavior observed under adult-simulating conditions may not fully represent the dynamic digestive environment of younger children. However, because the present formulation is primarily intended for older pediatric patients or adults, it was studied in the standard digestive model. According to the model results, the behavior of both substances in the GI tract depends on their physicochemical characteristics. Specifically, the release of the drugs from the chocolate/honey formulation, which differs significantly between the two APIs, highlights the significant influence of the medium (gastrointestinal fluids) on the kinetics of both drugs' dissolution. In this case and in order to consider the hydrolysis product of ACA, SAL, its release rate was calculated overall, summing both substances. Dipyridamole (weak base) is a poorly water-soluble substance that exhibits enhanced dissolution in acidic gastric conditions (Figure 7a), resulting in its supersaturation and then, during passage into the intestinal environment, its partial precipitation [59]. Notably, the presence of lipids and digestive enzymes, during digestion, has been shown to significantly enhance the solubility and supersaturation of weakly basic drugs, thereby affecting their release [60]. In contrast, aspirin, being a weak acid, displays poor solubility in acidic gastric conditions, potentially leading to precipitation in the stomach and associated gastrointestinal side effects [61]. As the environmental pH increases towards intestinal conditions, aspirin's solubility significantly improves, resulting in the notable increase in its release observed during the intestinal phase of the in vitro digestion experiment (Figure 7a). Figure 7: In vitro release (**a**) and permeability (**b**) profiles of dipyridamole and aspirin-salicylic acid encapsulated in chocolate-based formulations. Values represent mean \(\pm\) SD (\(n=3\)). Following in vitro digestion, permeability studies through cellulose membranes were performed to further evaluate the permeation potential of both drugs. Franz diffusion cells are commonly employed to study passive drug permeability, including applications in oral formulations [62].