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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].