*2.1.2 Preparation of oxidized chitosan (OCS)/chitosan (CS) hydrogels*

The procedure for preparation of the hydrogel was as follows: chitosan (0.1 g) was dispersed in 10 ml of (1% acetic acid) at pH = 4.8 in an ice bath under magnetic stirring until a clear solution was obtained. Afterwards, the drug (5-FU 10 mg, Caffeine 10 mg or Ascorbic acid 10 mg) was added into the solution and gently stirred until the complete dissolution for 30 min. The oxidized chitosan (60 mg) was added to the solution of chitosan soluble drug under continuous stirring to facilitate crosslinking between amino of chitosan (NH2) and aldehyde groups of chitosan (OCS). Then the 6% (w/v) NaHCO3 solution was slowly added to the solution in an ice bath under magnetic stirring to get homogeneous mixture at pH = 7 [56], and a transparent gel was obtained as shown in **Figure 4**. The hydrogel was washed with ethanol, and filtered to remove traces of unreacted reagents.

**Figure 3.** *Schematic representation of reaction between chitosan (CS) by sodium periodate.*

#### **Figure 4.**

*Schematic representation of the chemical (CS)/(OCS) cross-linking mechanism and the formation of the hydrogel.*
