**4. Chitosan polymer**

Chitosan is a hydrophilic, cationic polysaccharide soluble in dilute acids such as acetic acid and formic acid, due to protonated amine groups (NH3+ ) [75]. It is an N-acetylated derivative of chitin, a natural polysaccharide found in the shells of marine crustaceans. Chitin is chemically inert and thus has fewer applications that chitosan [77]. The acetamido group of chitin, (C2H4NO) can be turned into amino group to yield chitosan by the alkaline deacetylation of chitin. Chitosan is approved as safe by the United States Food and Drug Administration (US-FDA) for dietary use and wound dressing applications, but its toxicity increases with electrical charge and degree of deacetylation [17]. Chemically, it comprises of β- [1–4] -linked D-glucosamine and N-acetylated units (**Figure 4**).

The amine group has pKa of 6.2–6.5 [78]. At slightly acidic pH values, the amine groups (NH3+ ) become protonated, hence possessing the ability to effectively form electrostatic interactions with negatively charged species within mucin in the GIT [75]. Positively charged moieties of chitosan also interact with the tight junctions of the intestinal epithelial cells and thus modulate drug permeation and absorption through the interstitial space between epithelial cells [79]. Moreover, the existence of both hydroxyl and amino groups offers various possibilities for chemical modification. Chemical modifications give rise to different functional derivatives of chitosan like carboxylation, thiolation, alkylation, acylation etc. that further imparts desirable physiochemical and biopharmaceutical properties, such as solubility, adsorption and pH sensitivity in oral drug delivery [80]. For example, N-trimethyl chitosan chloride is developed to amplify the intestinal solubility of chitosan; thiolated chitosan is produced to augment the mucoadhesiveness of chitosan;

**Figure 4.** *Chemical structure of chitosan, comprising N-acetyl-D-glucosamine (right) and D-glucosamine (left) units.*

quaternization of chitosan reinforces its impact on the tight junctions of the GIT epithelium whilst grafting carboxylated chitosan with poly(methyl methacrylate) imparts increased pH sensitivity [81]. Physical modification through blending with other polymers may be used to enhance desirable physical properties. For example, blending of chitosan with polyethylene glycol (PEG) and polyvinyl alcohol (PVA) ameliorate the hydrophilic property of chitosan, while blending of chitosan with cellulose improves its antibacterial properties [82].
