Carbohydrate Polymers 82 (2010) 181–188 Contents lists available at ScienceDirect Carbohydrate Polymers journal homepage: www.elsevier.com/locate/carbpol Synthesis of cross-linked N-(2-carboxybenzyl)chitosan pH sensitive polyelectrolyte and its use for drug controlled delivery Konstantinos P. Koutroumanis a , Konstantinos Avgoustakis b , Dimitrios Bikiaris a,∗ a Laboratory of Polymer Chemistry and Technology, Department of Chemistry, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Macedonia, Greece b Laboratory of Pharmaceutical Technology, Department of Pharmacy, University of Patras, 26500 Patras, Greece article info Article history: Received 24 November 2009 Received in revised form 20 April 2010 Accepted 21 April 2010 Available online 29 April 2010 Keywords: Chitosan Schiff base pH-sensitive hydrogel Fluconazole Controlled-release abstract N-(2-Carboxybenzyl)chitosan (CBCS) polyelectrolyte was synthesized via a Schiff reaction of chitosan with 2-carboxybenzaldehyde, followed by reduction of the imine derivative with sodium borohydride. The polyampholyte chitosan derivative was cross-linked with glutaraldehyde leading to the formation of a pH-sensitive hydrogel. All prepared materials were characterized by FTIR, UV and 1 H NMR spectroscopies. The swelling behavior of the cross-linked N-(2-carboxybenzyl)chitosan hydrogel (CBCSG) was studied in aqueous solutions of varied pH (1, 5, 7 and 9). It was found that CBCSG swelled more in acidic solutions than in alkaline ones. Drug loading of fluconazole (a sparingly water-soluble drug) in CBCSG was prepared using the solvent evaporation method. WAXD data revealed that the drug was amorphous in the prepared formulations with 20% (w/w) drug content or less and crystalline at higher loading. Release of fluconazole from CBCSG was effectively sustained, indicating the suitability of the CBCSG to be used as a controlled- release system of fluconazole. The release rate was found to depend on drug loading and the pH of the release medium, which controlled the swelling capacity of the gel during drug release. © 2010 Elsevier Ltd. All rights reserved. 1. Introduction Chitosan (CS), a copolymer of -(1→4)-d-glucosamine and -(1→4)-N-acetyl-d-glucosamine, is the (partially) deacetylated product of chitin [poly--(1→4)-N-acetyl-d-glucosamine], the sec- ond most abundant natural occurring polysaccharide after cellulose (Kumar, Muzzarelli, Muzzarelli, Sashiwa, & Domb, 2004). Whereas chitin is insoluble in water due to the extensive hydrogen bond- ing of the acetyl group, chitosan is soluble in dilute acid solutions due to the ionization of the amino group and insoluble in solu- tions with pH > 4.5. Chitin, chitosan and their derivatives have been widely used in pharmaceutical systems, among numer- ous other applications (Kumar, 2000; Rinaudo, 2006; Shimono et al., 2002), on account of their lack of toxicity and excellent biocompatibility. Amongst the chitosan derivatives utilitized in pharmaceutical applications, of major importance is the N-alkylated chitosans. N- alkylation can be achieved via the reaction of chitosan with either an aldehyde or ketone followed by reduction, or via the reaction of chitosan with alkyl halides. However, the reaction of chitosan with alkyl halides usually leads to N,O-alkylated products (Kurita, 2001; Mourya & Inamdar, 2008). Carboxymethyl-chitosan (CMCS) ∗ Corresponding author. Tel.: +30 2310 997812; fax: +30 2310 997769. E-mail address: dbic@chem.auth.gr (D. Bikiaris). is a water-soluble chitosan derivative, soluble at both acidic and basic physiologic conditions, which is obtained from the reac- tion of chloroacetic acid and chitosan in alkaline medium under relative mild conditions (50–60 ◦ C). This conversion not only pro- vides carboxymethyl-chitosan with aqueous solubility, but also brings some useful chemical, physical and biological properties to carboxymethyl-chitosan, such as high viscosity and large hydro- dynamic volume, low toxicity, biocompatibility and antibacterial activity. These properties make carboxymethyl-chitosan an attrac- tive material for applications in food products, cosmetics and pharmaceuticals (Muzzarelli, 1988). The degree of substitution and molecular weight of carboxymethyl-chitosan plays an important role in drug delivery. Thus, nanoparticles based on carboxymethyl- chitosan with higher molecular weight and degree of substitution exhibited enhanced drug loading and lower rate of drug release (Shi, Du, Yang, Zhang, & Sun, 2006). A pH-sensitive chitosan derivative, N-(2-carboxybenzyl) chitosan (CBCS), has been synthesized from the reaction of chi- tosan with carboxybenzaldehyde (CBBA) and subsequent reduction of the imine derivative (CBCSS) (Muzzarelli, Tanfani, Marriotti, & Emanuelli, 1982; Lin, Chen, & Luo, 2007). In these studies, however, the imine derivative was not isolated and was reduced in situ (in the presence of unreacted carboxybenzaldehyde), rendering unclear exact chemical structure of the final product. A mixture of mono- and di-substituted products was probably synthesized. As the physicochemical and biological properties of the polymer depend on its structure, in order N-(2-carboxybenzyl)chitosan to 0144-8617/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.carbpol.2010.04.044