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CHAPTER – 1 INTRODUCTION Pharmaceutical excipients are the inactive ingredients used to impart particular attributes of a dosage form. Designing a successful dosage form requires a careful selection of a number of excipients in addition to the active pharmaceutical ingredient(s). Indian Pharmacopoeia, 2007 defines excipient as any innocuous substance added in preparing an official preparation, having no adverse influence on the therapeutic efficacy of the active ingredients, free from harmful organisms and not interferes with the tests and assays of the Pharmacopoeia. They ensure in vivo performance and are integral component of the drug formulation. They can also serve various therapeutic-enhancing purposes such as facilitating drug absorption or solubility or other pharmacokinetic considerations [Lesney, 2001]. The selection of the excipients for a particular dosage form is very critical with regard to its compatibility with the active pharmaceutical ingredients. They are essential resources for formulators in the pharmaceutical industry, as well as those interested in the formulation or production of confectionery, cosmetics and food products for incorporating desired properties in final product. Excipients are subdivided into various functional classifications depending on the their intended purpose such as diluents, binders, disintegrants, lubricants, glidants, emulsifying agents, solubilizing agents, sweetening agents, coating agents, antimicrobial preservatives, flavouring agents, colouring agents, etc. Polymers are macromolecules composed of repeating structural units of monomers connected by covalent bonds and are made by the process known as polymerization. A vast variety of natural, semi-synthetic and synthetic polymers are in use as pharmaceutical excipients. Natural polymers such as starch, gelatin, sodium alginate, xanthan gum and arabic gum are widely used materials in conventional and novel dosage forms. These materials are biocompatible, nontoxic, less expensive, biodegradable, eco-friendly and readily available [Bansal et al., 2011]. Examples of semi-synthetic polymers used as pharmaceutical excipients include cellulose derivatives such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylmethyl cellulose, carboxymethylcellulose sodium, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose acetate maleate, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate and various derivatives of chitin and chitosan, etc. Chitin and chitosan derivatives have recently found a vast variety of applications in fabrication of dosage forms as binder, coating agent, membrane forming agent, sustained release agent, etc [Draczynski, 2011; Filho et al., 2008; Jana et al., 2011; Murthy et al., 1987; Park & Park, 2001; Zohuriaan-Mehr, 2005]. Today fully synthetic polymers are available to serve specific purposes in drug delivey systems e.g., polymethacrylates have specific solubility properties adapted to the pH conditions of the digestive tract and polyacrylic acid (carbopol) is used as bioadhesive and matrix forming agent. Other synthetic polymers such as poly(methyl methacrylate), poly(vinyl alcohol), poly(vinyl pyrrolidone), poly(lactic acid), poly(glycolic acid), poly(ethylene glycol), etc. are very promising in the formulation of dosage forms [Kim, 2004]. Chitin, poly (β-(1→4)-N-acetyl-D-glucosamine), first identified in 1884, is a naturally occurring polysaccharide consisting of amino sugars. This biopolymer is synthesized by an extremely large number of living organisms and considering the amount of chitin produced annually in the world, it is the second most plentiful natural polymer, behind only cellulose [Kim, 2004; Kumar, 2000; Rinaudo, 2006]. Chitin occurs in nature as ordered crystalline microfibrils forming structural components in the exoskeleton of arthropods (e.g., crustacean shells of crab, shrimp and cuttlefish) and in the cell walls of fungi and yeast [Raabe et al., 2007; Rinaudo, 2008; Vincent & Wegst, 2004] and is associated with proteins and minerals such as calcium carbonate. It is also synthesized by some other living organisms in the lower plant and animal kingdoms (such as microfauna and plankton), where its function is to provide support to their physical structure [Kim, 2004; Kumar, 2000; Rinaudo, 2006]. Although chitin has wide presence in the nature, crab and shrimp shells are the main commercial sources of chitin, which are discarded as a waste material by sea food canning industries making its production economically feasible [Kumar, 2000]. Chitin is composed of repeating monomer units of 2-acetamido-2-deoxy-β-Dglucose connected through β(1→4) linkage, resembling cellulose, except that the hydroxyl groups in position 2 have been substituted by acetamido groups [Kim, 2004; Kumar, 2000]. However, about 16% of hydroxyl groups in position 2 are deacetylated [Kim, 2004]. It is a highly insoluble material resembling cellulose in its solubility and chemical reactivity. Like cellulose, it functions naturally as a structural polysaccharide. Chitin can be catabolized by the enzyme chitinase. Chitosan, the N-deacetylated derivative of chitin, is a polysaccharide formed of repeating monomer units of β(1→4) 2-amino-2-deoxy-D-glucose, although this N-deacetylation is almost never complete [Kim, 2004; Kumar, 2000]. Generally, more than 80% deacetylation can not be achieved without depolymerization and shortening of the polymer chains [Kim, 2004]. Cellulose is a homopolymer, while chitin and chitosan are heteropolymers (neither random nor block). The presence of high percentage of nitrogen (6.89%) in chitin and chitosan makes them useful chelating agent for commercial use [Kumar, 2000]. CH2OH O O HO NH (a) O n C CH3 NH2 CH2OH O HO O O HO CH2OH NH (b) O x C O y CH3 Fig. 1.1 Chemical structure of (a) chitin and (b) chitosan (the fraction of x units in the chain is less than 50%. In general, the fraction of x and y units in chain is about 20% and 80%, respectively and can vary with sources of chitin and processing methods.) In chitin, the degree of acetylation (DA) is typically 0.90 indicating the presence of some amino groups (as some amount of deacetylation might take place during extraction, chitin may contain about 5-15% amino groups) [Rinaudo, 2006]. The degree of N-acetylation, has a remarkable effect on chitin solubility and solution properties [Austin et al., 1981; Dong et al., 2002; Rinaudo, 2006]. In chitosan, the typical value of DA is less than 0.35. It is, thus, a copolymer composed of glucosamine and N-acetylglucosamine [Pillai et al., 2009]. A sharp nomenclature border between chitin and chitosan has not been defined based on the degree of N-deacetylation [Kumar, 2000; Kumirska et al., 2010]. According to the European Chitin Society, chitin and chitosan should be classified on the basis of their solubility and insolubility in 0.1 M acetic acid; the soluble material is named chitosan, whereas chitin is insoluble [Roberts, 2007]. Despite the limitation in the reactivity and processability of these naturally abundant polymers, chitin and chitosan are suitable functional materials by virtue of their excellent properties such as biocompatibility, biodegradability, nontoxicity, adsorption properties, etc. [Kumar, 2000; Muzzarelli & Muzzarelli, 2005]. Amino and hydroxyl groups in chitosan readily react to produce varieties of chitosan derivatives to modify its properties to meet various application requirements [Kim, 2004]. Chitin and chitosan are having immense structural possibilities for chemical and mechanical modifications to generate novel properties, functions and applications especially in biomedical area [Pillai et al., 2009]. The positive attributes of excellent biocompatibility and admirable biodegradability with ecological safety and low toxicity with versatile biological activities such as antimicrobial activity and low immunogenicity (despite the presence of nitrogen) have provided ample opportunities for further development [Hirano, 1999; Jayakumar et al., 2007; Kumar, 2000; Kurita, 2006; Mourya & Inamdar, 2008; Rinaudo, 2008; Yi et al., 2005]. Chitin and chitosan have attracted a lot of attention of various researchers as shown by the number of scientific publications related to chitin and chitosan, recently. Almost 119 reviews, 2040 research articles and 11804 patents have been published after year 2000 [Aranaz et al., 2009]. Great interest has been generated in chitin and chitosan not only as an under utilized resource but also as a new functional biomaterial with high potential of applicability in diverse fields [Kumar et al., 2004; Kurita, 1998].