Chitosan Derivatives - Chitosan Based Hydrogels: Functions and Applications - page 62

NH 2 +

HS -NH 3

RNH 2 (Chitosan)

S NH 2 +Cl-

S

NR

HN

R

2-iminothiolane

N-substituted iminothiolane

Chitosan thiomer

Figure 2.18
Instability of the chitosan-4-thiobutylamidine conjugate.

almost excluded. Alternatively, the coupling reaction can be performed under inert
conditions. In the case of the formation of amidine bonds, 2-iminothiolane is used as a
coupling reagent. It offers the advantage of a simple one-step coupling reaction. In addi-
tion, the thiol group of the reagent is protected from oxidation because of the chemical
structure of the reagent. However, storage stability studies under nitrogen showed an
insufficient stability of thiomer, which resulted in a decrease of free thiol moieties. This
might be due to the formation of N -chitosanyl-substituted 2-iminothiolane structures. This
undesired side-reaction occurs after the derivatization of different amines with 2-imino-
thiolane. It involves the loss of ammonia and yields recyclized N-substituted 2-iminothio-
lane (Figure 2.18) [189]. To achieve the same properties as chitosan-4-thiobutyl-amidine
and to overcome at the same time its insufficient stability, chemical modification of chito-
san can be done with isopropyl- S -acetylthioacetimidate HCl (i-PATAI), resulting in chito-
san-thioethylamidine conjugate [182]. The nucleophilicity of amino groups is dictated by
the protonation state making the reaction pH dependent. The reactions can be carried out
at pH 6.5-7.0, at which pH value the oxidation process of thiol groups is decreased and
chitosan is soluble as well [190]. This imidoester reacts rapidly with an amine—maximum
for 1.5 h in comparison with the reaction with 2-iminothiolane, which ends after 24 h under
continuous stirring at room temperature [184]. The short chain of i-PATAI excludes theo-
retically the possibility of yielding cyclic nonthiol products. Various properties of chitosan
are improved by this immobilization of thiol groups allocating it to a promising new cat-
egory of thiomers used in particular for the noninvasive administration of hydrophilic
macromolecules.
A drawback of the thiomers developed so far is their pH-dependent reactivity. The reac-
tive form of thiomers is the thiolate anion. The p K a of alkyl thiols is in the range of 8-10.
This means that thiomers will be most reactive in a pH range slightly above the physiologi-
cal intestinal pH. 6-Mercaptonicotinic acid was chosen to develop a novel thiomer with a
pH-independent action mechanism. Due to its particular structure, this compound has
two tautomeric structures: thiol (S-H) and thione (C=S). In polar solvents such as water,
the thione form (C=S) is the most predominant structure. This structure can react with a
disulfide bond both as a nucleophile and as a proton donor. Therefore, disulfide bonds can
be formed even without thiol groups being available on the polymer in the form of thiolate
anions. The newly synthesized chitosan-6-mercaptonicotinic acid conjugate showed excel-
lent in situ gelling properties without the addition of any oxidizing species. Moreover, in
contrast to all other thiolated polymers, the gelling properties are pH independent. This
property might be of considerable advantage for drug delivery applications requiring
in situ gelling properties where the pH could be different according to age or individual
differences, such as the vagina.
Thiolated chitosans have recently emerged as new biomaterials for delivering drugs
throughout the body. The covalent attachment of various compounds bearing sulfhydryl
groups to chitosan leads to a powerful modification. Thiolated chitosans exhibit compara-
tively strong mucoadhesive and in situ gelling properties, enabling controlled drug release.