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The aim of this study was to improve the properties of chitosan as excipient in drug delivery systems by the covalent attachment of thiol moieties. This was achieved by the modification of chitosan with 2-iminothiolane. The resulting chitosan–4-thio-butyl-amidine conjugates (chitosan–TBA conjugates) displayed up to 408.9±49.8 μmol thiol groups per gram polymer. Because of the formation of disulfide bonds based on an oxidation process of the immobilized thiol groups under physiological conditions, chitosan–TBA conjugates exhibit in situ gelling properties. After less than 2 h, 1.5% (m/v) chitosan–TBA conjugate solutions of pH 5.5 formed covalently cross-linked gels. The viscosity increased in positive correlation with the amount of thiol groups immobilized on chitosan. In addition, also the mucoadhesive properties were strongly improved by the covalent attachment of thiol groups on chitosan. The adhesion time of tablets based on the unmodified polymer on freshly excised porcine intestinal mucosa spanned on a rotating cylinder in an artificial intestinal fluid was extended more than 140-fold by using the thiolated version. Drug release studies out of tablets comprising the chitosan–TBA conjugate demonstrated that an almost zero-order release kinetic was achieved for the model drug clotrimazole within the first 6 h. The modification of chitosan with 2-iminothiolane leads, therefore to thiolated polymers, which represent a promising tool for the development of in situ gelling and/or mucoadhesive drug delivery systems.