Chitosan as an enabling excipient for drug delivery systems: I. Molecular modifications

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Abstract

Chitosan was physicochemically modified for its potential use as a matrix for an implantable antibiotic delivery system that could sustain bactericidal concentrations in the vicinity of an implant or prosthesis. Deacetylation and depolymerization of chitosan were implemented in order to increase the number or accessibility of the reactive amino groups on the polymer backbone for better polymer–drug interaction. The deacetylation process involved reaction of particulate chitosan/depolymerized chitosan with alkali. The rate of deacetylation of chitosan was directly proportional to the reaction temperature up to 80°C; beyond 80°C, rapid degradation of the polymer occurred. The depolymerization of chitosan involved acid digestion of the polymer followed by application of mechanical agitation. This depolymerized product, although water insoluble, possessed a molecular weight that was one to two orders of magnitude lower than that of commercially available chitosans. These products not only exhibited improved reactivity, but also showed increased crystallinity when compared with the parent chitosan. The reactivity was found to be inversely proportional to chitosan’s molecular weight. The depolymerization and deacetylation treatments afforded formation of chitosan having a greater number of amino groups available for interactions with the anionic actives.

Introduction

Chitosan is a cationic biopolymer that is bioadhesive, biocompatible and biodegradable [1]. These unique properties make it an attractive carrier for biomedical applications. Orally administered [2] as well as implantable delivery systems [3], [4] containing chitosan as a drug carrier have been prepared to effect sustained release of the drug. Modulation of drug release has been achieved by drug–chitosan complexation involving ionic [2], [5], [6], [7] or covalent interactions [8]. While the focus for ionic interactions of chitosan involves the amino groups of its glucosamine residues, covalent interactions often involve other sites as well (e.g. the CH2OH moieties).

Chemical treatments that increase the degree of deacetylation of chitosan (and subsequently its complexation capability) have been widely studied [9], [10], [11]. Also, there is ample evidence in the literature attesting to the effect of molecular weight of chitosan on its complexation behavior. With respect to polymeric systems containing chitosan and oxidized cellulose, Domszy and Roberts [12] observed an increase in equilibrium adsorption of chitosan on oxidized cellulose with decreasing molecular weights of chitosan. While investigating the efficiency of different chitosans for removing proteins from cheese whey, Wu et al. [13] found that chitosan’s effectiveness in coagulating solids and proteins was inversely proportional to its molecular weight.

This study reports on some physicochemical modifications (e.g. deacetylation and depolymerization) of chitosan that will allow modulation of its complexation capability, and thus make it suitable as a matrix for various delivery systems.

Section snippets

Materials

Chitin was generously donated by Protan Co. (Drammen, Norway). Chitosan, d-glucosamine hydrochloride and ninhydrin reagent were purchased from Sigma Chemical Company (St. Louis, MO). Glacial acetic acid, hydrochloric acid, sodium acetate, sodium chloride and sodium hydroxide were used as supplied by Fisher Scientific (Fair Lawn, NJ).

N-Deacetylation of chitin or chitosan

The alkaline deacetylation of chitin was achieved using the method of Chen [11], which employs ‘particulate’ chitin as the source of the biopolymer. Since the

N-Deacetylation of chitin or chitosan

The concentration of sodium hydroxide in the penetrating solution could be expected to play a significant role in the deacetylation process. However, when 30% w/v sodium hydroxide solution was used in the deacetylation process, minimal or no deacetylation occurred.

Using a higher alkali concentration, i.e. 50%, in the deacetylation reaction resulted in measurable increases in the degree of deacetylation of chitin/chitosan. The study of the temperature dependence of the deacetylation reaction

Conclusions

Among the physicochemical modifications of chitosan studied, the deacetylation reaction proceeded at the fastest rate at 80°C. At higher temperatures, rapid polymer degradation was noticed. The increase in the degree of deacetylation was linear with the square root of time, suggesting the presence of a diffusion-controlled deacetylation process.

Among the various depolymerization variables studied, acid digestion time was found to be the only factor which controlled the molecular weight of the

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