A Review of Chitin and Chitosan Applications

Reactive & Functional Polymers 46 (2000) 1–27www.elsevier.com/ locate / react

Review

qA review of chitin and chitosan applications

*Majeti N.V. Ravi KumarDepartment of Chemistry, University of Roorkee, Roorkee 247 667, India

Received 24 January 2000; received in revised form 20 June 2000; accepted 25 June 2000

Abstract

Chitin is the most abundant natural amino polysaccharide and is estimated to be produced annually almost as much ascellulose. It has become of great interest not only as an underutilized resource, but also as a new functional material of highpotential in various fields, and recent progress in chitin chemistry is quite noteworthy. The purpose of this review is to take acloser look at chitin and chitosan applications. Based on current research and existing products, some new and futuristicapproaches in this fascinating area are thoroughly discussed. 2000 Elsevier Science B.V. All rights reserved.

Keywords: Beads; Biotechnology; Chitin; Chitosan; Controlled drug delivery; Fibers; Nanoparticles; Hydrogels; Tablets; Transdermaldevices

1. Introduction position C-2 replaced by an acetamido group.Like cellulose, it functions naturally as a struc-

Chitin, a naturally abundant mucopolysac- tural polysaccharide. Chitin is a white, hard,charide, and the supporting material of crusta- inelastic, nitrogenous polysaccharide and theceans, insects, etc., is well known to consist of major source of surface pollution in coastal2-acetamido-2-deoxy-b-D-glucose through a b areas. Chitosan is the N-deacetylated derivative(1 → 4) linkage. Chitin can be degraded by of chitin, although this N-deacetylation is al-chitinase. Its immunogenicity is exceptionally most never complete. A sharp nomenclaturelow, in spite of the presence of nitrogen. It is a with respect to the degree of N-deacetylationhighly insoluble material resembling cellulose has not been defined between chitin andin its solubility and low chemical reactivity. It chitosan [1,2]. The structures of cellulose, chitinmay be regarded as cellulose with hydroxyl at and chitosan are shown in Fig. 1. Chitin and

chitosan are of commercial interest due to theirhigh percentage of nitrogen (6.89%) compared

qThis paper is dedicated to Professor M.N.V. Prasad, Ph.D., to synthetically substituted cellulose (1.25%).FNIE (New Delhi), DSc. (hc Colombo), School of Life Sciences,

This makes chitin a useful chelating agent [1].University of Hyderabad, Hyderabad, India, who inspired me withhis scientific approach, honesty and human warmth. As most of the present-day polymers are syn-

*Post Bag No. 29, Roorkee 247 667, India. Fax: 191-1332- thetic materials, their biocompatibility and73560.

biodegradability are much more limited thanE-mail address: [email protected] (M.N.V. RaviKumar). those of natural polymers such as cellulose,

1381-5148/00/$ – see front matter 2000 Elsevier Science B.V. All rights reserved.PI I : S1381-5148( 00 )00038-9

2 M.N.V. Ravi Kumar / Reactive & Functional Polymers 46 (2000) 1 –27

radability, non-toxicity, adsorption properties,etc.

Recently, much attention has been paid tochitosan as a potential polysaccharide resource[5]. Although several efforts have been reportedto prepare functional derivatives of chitosan bychemical modifications [6–8], very few attainedsolubility in general organic solvents [9,10] andsome binary solvent systems [11–13]. Chemi-cally modified chitin and chitosan structuresresulting in improved solubility in general or-ganic solvents have been reported by manyworkers [14–23]. The present review is anattempt to discuss the current applications andfuture prospects of chitin and chitosan.

2. Processing of chitin and chitosan

Chitin is easily obtained from crab or shrimpshells and fungal mycelia. In the first case,chitin production is associated with food indus-Fig. 1. Structures of cellulose, chitin and chitosan.

tries such as shrimp canning. In the second case,the production of chitosan–glucan complexes is

chitin, chitosan and their derivatives. However, associated with fermentation processes, similarthese naturally abundant materials also exhibit a to those for the production of citric acid fromlimitation in their reactivity and processability Aspergillus niger, Mucor rouxii, and Strep-[3,4]. In this respect, chitin and chitosan are tomyces, which involves alkali treatment yield-recommended as suitable functional materials, ing chitosan–glucan complexes. The alkali re-because these natural polymers have excellent moves the protein and deacetylates chitin simul-properties such as biocompatibility, biodeg- taneously. Depending on the alkali concentra-

Scheme 1.

M.N.V. Ravi Kumar / Reactive & Functional Polymers 46 (2000) 1 –27 3

tion, some soluble glycans are removed [24]. 4. Properties of chitin and chitosanThe processing of crustacean shells mainly

Most of the naturally occurring polysac-involves the removal of proteins and the disso-charides, e.g. cellulose, dextran, pectin, alginiclution of calcium carbonate which is present inacid, agar, agarose and carragenans, are neutralcrab shells in high concentrations. The resulting

chitin is deacetylated in 40% sodium hydroxide or acidic in nature, whereas chitin and chitosanat 1208C for 1–3 h. This treatment produces are examples of highly basic polysaccharides.70% deacetylated chitosan (Scheme 1). Their unique properties include polyoxysalt

formation, ability to form films, chelate metalions and optical structural characteristics [29].

3. Economic aspects Like cellulose, chitin functions naturally as astructural polysaccharide, but differs from cellu-The production of chitin and chitosan islose in its properties. Chitin is highly hydro-currently based on crab and shrimp shellsphobic and is insoluble in water and mostdiscarded by the canning industries in Oregon,organic solvents. It is soluble in hexafluoro-Washington, Virginia and Japan and by variousisopropanol, hexafluoroacetone, chloroalcoholsfinishing fleets in the Antarctic. Several coun-in conjugation with aqueous solutions of miner-tries possess large unexploited crustacean re-al acids [24] and dimethylacetamide containingsources, e.g. Norway, Mexico and Chile [25].5% lithium chloride. Chitosan, the deacetylatedThe production of chitosan from crustaceanproduct of chitin, is soluble in dilute acids suchshells obtained as a food industry waste isas acetic acid, formic acid, etc. Recently, the geleconomically feasible, especially if it includesforming ability of chitosan in N-methylmor-the recovery of carotenoids. The shells containpholine N-oxide and its application in controlledconsiderable quantities of astaxanthin, a carot-drug release formulations has been reportedenoid that has so far not been synthesized, and[30–32]. The hydrolysis of chitin with concen-which is marketed as a fish food additive intrated acids under drastic conditions producesaquaculture, especially for salmon.relatively pure D-glucosamine.To produce 1 kg of 70% deacetylated

The nitrogen content of chitin varies from 5chitosan from shrimp shells, 6.3 kg of HCl andto 8% depending on the extent of deacetylation,1.8 kg of NaOH are required in addition towhereas the nitrogen in chitosan is mostly in thenitrogen, process water (0.5 t) and coolingform of primary aliphatic amino groups.water (0.9 t). Important items for estimating theChitosan, therefore, undergoes reactions typicalproduction cost include transportation, whichof amines, of which N-acylation and Schiffvaries depending on labor and location. In India,reaction are the most important. Chitosan de-the Central Institute of Fisheries Technology,

Kerala, initiated research on chitin and chitosan. rivatives are easily obtained under mild con-From their investigation, they found that dry ditions and can be considered as substitutedprawn waste contained 23% and dry squilla glucans.contained 15% chitin [26]. They have also N-Acylation with acid anhydrides or acylreported that the chitinous solid waste fraction halides introduces amido groups at the chitosanof the average Indian landing of shell fish nitrogen. Acetic anhydride affords fullyranges from 60 000 to 80 000 tonnes [27,28]. acetylated chitins. Linear aliphatic N-acylChitin and chitosan are now produced commer- groups above propionyl permit rapid acetylationcially in India, Japan, Poland, Norway and of hydroxyl groups. Higher benzoylated chitin isAustralia. The worldwide price of chitosan (in soluble in benzyl alcohol, dimethylsulfoxide,small quantities) is ca. US$7.5 /10 g (Sigma and formic acid and dichloroacetic acid. The N-Aldrich price list). hexanoyl, N-decanoyl and N-dodecanoyl deriva-


tives have been obtained in methanesulfonic the universally accepted non-toxic N-de-acid [33,34]. acetylated derivative of chitin, where chitin is

At room temperature, chitosan forms al- N-deacetylated to such an extent that it becomesdimines and ketimines with aldehydes and soluble in dilute aqueous acetic and formicketones, respectively. Reaction with ketoacids acids. In chitin, the acetylated units prevailfollowed by reaction with sodium borohydride (degree of acetylation typically 0.90). Chitosanproduces glucans carrying proteic and non- is the fully or partially N-deacetylated derivativeproteic amino groups. N-Carboxymethyl of chitin with a typical degree of acetylation ofchitosan is obtained from glyoxylic acid. Exam- less than 0.35. To define this ratio, attemptsples of non-proteic amine acid glucans derived have been made with many analytical toolsfrom chitosan are the N-carboxybenzyl [35–44], which include IR spectroscopy,chitosans obtained from o- and p-phthalal- pyrolysis gas chromatography, gel permeationdehydic acids [24,25]. Chitosan and simple chromatography and UV spectrophotometry,

1aldehydes produce N-alkyl chitosan upon hydro- first derivative of UV spectrophotometry, H-13genation. The presence of the more or less NMR spectroscopy, C solid state NMR, ther-

bulky substituent weakens the hydrogen bonds mal analysis, various titration schemes, acidof chitosan; therefore N-alkyl chitosans swell in hydrolysis and HPLC, separation spectrometrywater in spite of the hydrophobicity of the alkyl methods and, more recently, near-infrared spec-chains, but they retain the film forming property troscopy [45].of chitosan [1].

4.1.2. Molecular weightChitosan molecular weight distributions have4.1. Physical and chemical characterization

been obtained using HPLC [46]. The weight-The structural details of cellulose, chitin and average molecular weight (M ) of chitin andw

chitosan are shown in Fig. 1. Cellulose is a chitosan has been determined by light scatteringhomopolymer, while chitin and chitosan are [47]. Viscometry is a simple and rapid methodheteropolymers. Neither random nor block for the determination of molecular weight; theorientation is meant to be implied for chitin and constants a and K in the Mark–Houwinkchitosan. The properties of chitin and chitosan equation have been determined in 0.1 M aceticsuch as the origin of the material (discussed in acid and 0.2 M sodium chloride solution. Thethe previous section), the degree of N-deacetyla- intrinsic viscosity is expressed astion, molecular weight and solvent and solution

a 23 0.93properties are discussed in brief. Glycol chitin, a [h] 5 KM 5 1.81 3 10 Mpartially O-hydroxyethylated chitin, was thefirst derivative of practical importance; other

The charged nature of chitosan in acid solventsderivatives and their proposed uses are shown inand chitosan’s propensity to form aggregationTable 1.complexes require care when applying theseconstants. Furthermore, converting chitin intochitosan lowers the molecular weight, changes4.1.1. Degree of N-acetylationthe degree of deacetylation, and thereby altersAn important parameter to examine closely isthe charge distribution, which in turn influencesthe degree of N-acetylation in chitin, i.e. thethe agglomeration. The weight-average molecu-ratio of 2-acetamido-2-deoxy-D-glucopyranose

6 6lar weight of chitin is 1.03310 to 2.5310 ,to 2-amino-2-deoxy-D-glucopyranose structuralbut the N-deacetylation reaction reduces this tounits. This ratio has a striking effect on chitin

5 5solubility and solution properties. Chitosan is 1310 to 5310 [48].


Table 1Chitin derivatives and their proposed uses

Derivative Examples Potential uses

N-Acyl chitosans Formyl, acetyl, propionyl, butyryl, hexanoyl, Textiles, membranesoctanoyl, decanoyl, dodecanoyl, tetradecanoyl, and medical aidslauroyl, myristoyl, palmitoyl, stearoyl, benzoyl,monochloroacetoyl, dichloroacetyl, trifluoroacetyl,carbamoyl, succinyl, acetoxybenzoyl

N-Carboxyalkyl N-Carboxybenzyl, glycine-glucan (N-carboxy- Chromatographic(aryl) chitosans methyl chitosan), alanine glucan, phenylalanine media and metal

glucan, tyrosine glucan, serine glucan, glutamic ion collectionacid glucan, methionine glucan, leucine glucan

N-Carboxyacyl From anhydrides such as maleic, itaconic, acetyl- ?chitosans thiosuccinic, glutaric, cyclohexane 1,2-dicarbox-

ylic, phthalic, cis-tetrahydrophthalic, 5-norbo-rnene-2,3-dicarboxylic, diphenic, salicylic, tri-mellitic, pyromellitic anhydride

o-Carboxyalkyl o-Carboxymethyl, crosslinked o-carboxymethyl Molecular sieves,chitosans viscosity builders,

and metal ion collec-tion

Sugar derivatives 1-Deoxygalactic-1-yl-, 1-deoxyglucit-1-yl-, ?1-deoxymelibiit-1-yl-, 1-deoxylactit-1-yl-,1-deoxylactit-1-yl-4(2,2,6,6-tetramethylpiperidine--1-oxyl)-, 1-deoxy-69-aldehydolactit-1-yl-,1-deoxy-69-aldehydomelibiit-1-yl-, cellobiit-1-yl-chitosans, products obtained from ascorbic acid

Metal ion chelates Palladium, copper, silver, iodine Catalyst, photography,health products, andinsecticides

Semisynthetic resins Copolymer of chitosan with methyl methacrylate, Textilesof chitosan polyurea-urethane, poly(amideester), acrylamide-

maleic anhydride

Natural polysacchar- Chitosan glucans from various organisms Flocculation andide complexes, metal ion chelationmiscellaneous Alkyl chitin, benzyl chitin Intermediate, serine

protease purificationHydroxy butyl chitin, cyanoethyl chitosan Desalting filtration,

dialysis and insulatingpapers

Hydroxy ethyl glycol chitosan Enzymology, dialysisand special papers

Glutaraldehyde chitosan Enzymeimmobilization

Linoelic acid–chitosan complex Food additive andanticholesterolemic

Uracylchitosan, theophylline chitosan, adenine-chitosan, chitosan salts of acid polysaccharides,chitosan streptomycin, 2-amido-2,6-diaminohep-tanoic acid chitosan


4.1.3. Solvent and solution properties the first solutions of chitin that could be formedBoth cellulose and chitin are highly crys- into a ‘ropy-plastic’ state in 1926. He prepared

talline, intractable materials and only a limited the solution using inorganic salts capable ofnumber of solvents are known which are applic- strong hydration [49], such as LiCNS,able as reaction solvents. Chitin and chitosan Ca(CNS) , CaI , CaBr , CaCl , etc. After this2 2 2 2degrade before melting, which is typical for report, many solvent systems including organicpolysaccharides with extensive hydrogen bond- solvents and mixtures of inorganic salts anding. This makes it necessary to dissolve chitin organic solvents came into existence.and chitosan in an appropriate solvent system to To help the dissolution of chitin, it was N-impart functionality. For each solvent system, deacetylated in 5% caustic soda at 608C for 14polymer concentration, pH, counterion concen- days [50]. Another procedure for N-deacetyla-tration and temperature effects on the solution tion was to place the chitin in an autoclave for 3viscosity must be known. Comparative data h at 1808C and 10 atm pressure. It was pointedfrom solvent to solvent are not available. As a out that 6 to 10% of solids of N-deacetylatedgeneral rule, the maximum amount of polymer chitin can be brought into acidic solution atis dissolved in a given solvent towards a room temperature. Aqueous acetic acid washomogeneous solution. Subsequently, the poly- found to be suitable for this purpose.mer is regenerated in the required form (dis- After passing the polymer solutions through acussed in the following sections). A coagulant is filter press to remove impurities, fibres wererequired for polymer regeneration or solidifica- spun. Chemicals incompatible with chitin weretion. The nature of the coagulant is also highly suggested as coagulants. The resultant fibresdependent on the solvent and solution properties were washed and dried under tension. The finalas well as the polymer used [54,75]. product fibres had a round- to heart-shaped

cross section with a tensile breaking load of 352kg/mm (345 Pa). The fibres possessed a dull

5. Chitin and its derivatives in fibre luster similar to natural silk, leading to theformation suggestion that the N-deacetylated chitin fibres

would make good artificial hair. The collection5.1. Natural microfibriller arrangementand recycling of chitin from small-scale con-sumers was also suggested. Clark and SmithChitin has been known to form microfibrillarreported a procedure for producing fibres byarrangements in living organisms. These fibrilsdissolution of chitin at 958C in presaturatedare usually embedded in a protein matrix andsolutions of lithium thiocyanate (saturated 608C)have diameters from 2.5 to 2.8 nm. Crustacean[51]. No tensile properties or solution concen-cuticles possess chitin microfibrils with diame-trations were reported. However, X-ray analysisters as large as 25 nm. The presence of mi-showed a high degree of orientation. Solventcrofibrils suggests that chitin has characteristicsremoval was not successful even at 2008C.which make it a good candidate for fibreLithium iodide was implied to have behaved inspinning. To spin chitin or chitosan fibres, thethe same manner. A ratio of 5 mol lithiumraw polymer must be suitably redissolved afterthiocyanate per mole anhydroglucose unit wasremoval of extraneous material such as calciumfound to exist. This is comparable to thecarbonate and proteins, which encase the mi-cellulose–lithium thiocyanate compound. Cellu-crofibrils.lose solubility and the role of solvate / saltcomplexes have been reviewed in detail [52,53].5.2. Fibre formation — in retrospectionRecently, Rathke and Hudson published a re-

Numerous methods of spinning chitin fibres view highlighting the ability of chitin andhave been reported since Von Weimarn reported chitosan as fibre and film formers [54].


5.3. Novel solvent spin systems suggested as well as dissolution below roomtemperature. Fibres were extruded through a

5.3.1. Halogenated solvent spin system spinneret of 0.04 and 0.06 mm diameter into anIn 1975, Austin suggested organic solvents acetone coagulation bath followed by a metha-

containing acids for the direct dissolution of nol bath. The tensile strength of dried filamentschitin. Such a system was chloroethanol and was in the range of 1.67 to 3.1 g/d with ansulfuric acid. The precipitation of chitin in elongation from 8.7 to 20.0%. The strength offibrillar form in water, methanol, or aqueous the fibres was improved by leaving them in aammonium hydroxide was mentioned, but no 0.5 g/ l aqueous caustic soda solution for 1 h.fibre tensile data were presented [55]. The resultant tensile strengths were 2.25 to 3.20

In 1975, Brine and Austin suggested tri- g /d with elongations of 19.2 to 27.3%, respec-chloroacetic acid (TCA) as a chitin solvent. tively [57]. Kifune and co-workers further sug-Chitin was pulverized and two parts by weight gested that these chitin filaments were suitablewere added to 87 parts by weight of a solvent as absorbable surgical suture [58]. However,mixture containing 40% TCA, 40% chloral TCA is very corrosive and degrades the poly-hydrate (US Department of Justice, Drug En- mer molecular weight. The breaking elongationsforcement Agency, class IV controlled sub- suggest that the halogenated solvents act asstance), and 20% methylene chloride over a plasticizers.period of 30–45 min. A filament was extruded Fuji Spinning Company dissolved chitosan infrom this solution using a hypodermic needle a mixture of water and dichloroacetic acidand acetone as the coagulant. The filament was (DCA). The 6.44% chitosan acetate salt solutionthen neutralized with potassium hydroxide viscosity was 410 poise. The dope was extruded(KOH) in 2-propanol followed by washing in through a platinum nozzle (30 holes of 0.2 mmdeionized water. The filaments were then cold diameter each) into basic CuCO –(NH )OH3 4

drawn. Two tensile breaks were taken at 60% solution to form fibres. Denier and tensilerelative humidity and room temperature. The properties were not reported [59].first was from a filament with a cross section of Tokura and co-workers used a combination of0.0830.10 mm, yielding a tensile strength of 72 formic acid (FA), DCA and diisopropyl ether as

2kg/mm (710 Pa) and a breaking elongation of a solvent system. Chitin was cycled several13%. The second filament had a cross section of times from 2208C to room temperature in FA,0.01430.740 mm, indicating a collapsed core followed by addition of a small amount ofstructure. It had a tensile strength of 104 kg/ DCA. Diisopropyl ether was then added to

2mm (1026 Pa) and a breaking elongation of reduce the solution viscosity to below 199 poise44% [56]. Syringing a filament cannot be and tensile properties were also reported [60]. Itinterpreted as conclusive evidence for a possible is noteworthy that the wet strength drops towet spinning process. While syringe extrusion below 0.50 g/d but that the elongation increasesmight indicate the selection of a coagulant, it to 13%.would be rather surprising to obtain meaningful A TCA/dichloromethane spin system is alsotensile data. Shear forces in a spinneret are described by the Unitika Co. Three parts chitinmuch greater than those experienced in a sy- were dissolved in 50 parts TCA and 50 partsringe tip. dichloromethane. The defoamed dope was ex-

Kifune and co-workers suggested dissolving truded into acetone before wind-up. The bob-chitin in TCA and a chlorinated hydrocarbon bins were neutralized with KOH, washed withsuch as chloromethane, dichloromethane, and water, and dried. The fibres had a tensile1,1,2-trichloroethane. The TCA concentration strength of 2 g/d and 0.5–20 denier [61].should be kept between 25 and 75%. A con- Unitika Co. also used the TCA/chloral hy-centration range between 1 and 10% chitin was drate /dichloroethane solvent system for chitin.


Five parts were dissolved in 100 parts of a 4:4:2 upon short exposures. Chlorohydrocarbons areTCA/chloral hydrate /dichloroethane solvent increasingly environmentally unacceptable sol-mixture and extruded through a 0.06 mm nozzle vents. Hexafluoro-2-propanol and hexafluoro-into acetone. The fibres were treated with acetone sesquihydrate are toxic. Formic acid canmethanolic NaOH. The optimum fibres gave a act as a sensitizer.tenacity of 3.2 g /d with an elongation of 20%[62]. Unitika Co. followed this up with another 5.3.2. Amide–LiCl systempatent using a 60:40 TCA/trichloroethylene In 1978, Rutherford and Austin summarizedspin dope mixture. Tensile properties were the problems encountered in finding a solventunavailable [63]. In 1983, Unitika Co. showed system for chitin [65]. Austin suggested N,N-that a dope consisting of three parts chitin, 50 dimethylacetamide (DMAc)–5% LiCl or N-parts TCA, and 50 parts dichloromethane could methyl-2-pyrrolidone (NMP)–5% LiCl as sol-be spun at a rate of 1.7 ml /min under 25 vents for chitin. A solution of 5% w/v was

2kg/cm pressure into acetone to form filaments. obtained within 2 h with these systems. AThe extrusion die had holes of 0.07 mm diam- filament was extruded from the solution using aeter, indicating a jet velocity of 8.8 m/min and 15-gauge needle into an acetone coagulationa take-up of 5 m/min. The coagulation bath was bath. This was followed by more washing andmaintained at 188C. The filaments were washed drawing in acetone. The final filament waswith acetone at 188C for 10 min, rewound at 4.5 washed in deionized water. Tensile propertiesm/min, then neutralized, washed and dried. The were obtained at 60% R.H. and room tempera-multifilament product had a total denier of 150 ture at an applied stress of 0.1 cm/min. Thewith a tenacity of 2.65 g/d [63]. A similar resultant dry tensile strengths for different crabsystem using four parts chitin in the same and shrimp species ranged from 24 to 60 kg/

2solvent but a 40-hole die of 0.08 mm diameter mm (236–592 Pa) [66].each was also used. The jet velocity was 10.4 Russian researchers spun chitin fibres out ofm/min into a 258C acetone bath. A rewinding at DMAc/NMP solutions containing 5% chitin7 m/min followed the first take-up roll at 5 and 5% LiCl (based on chitin content). Thesem/min. The total denier was 175; however, no fibres were drawn in a 50:50 ethanol /ethylenetensile properties were reported [64]. glycol bath, giving an average yield strength of

Some of the halogenated solvent systems 390 MPa with 3% elongation. An initialattained dry tenacities of above 3 g/d; however, modulus of 2 GPa was also reported. Scanningthe low wet tenacities were still undesirable. electron microscopy showed fibres with a roundAlthough the fibre characterization was much fibrillar cross section [67]. A follow-up studybetter for these systems, the polymer characteri- showed a decrease in the elasticity modulus andzation lacked molecular weight as well as relative elongation with increase in the degreedegree of N-acetylation formation. Solution of N-acetylation (12–30%). From X-ray analy-properties would be hard to obtain due to rapid sis, an increase in the amount of amorphouschitin degradation in these solvents. Although regions was observed with increase in degree ofanhydrous coagulation baths were used and acetylation [68].compared, fibres were neutralized in aqueous The amide–lithium systems showed some ofmedia. A study in completely anhydrous sys- the best dry tenacities, although they still lacktems would be of interest, since it may lead to adequate wet tenacities. The low wet tenacitiesmore densely consolidated fibres. The im- are probably due to low crystallinity and poorplementation of these spin systems represents a consolidation of the fibre. The fibres and spinproblem due to the nature of the solvents. TCA dopes were well characterized but the polymersand DCA are corrosive and degrade the polymer used to prepare these dopes were not. Some


coagulation studies were carried out but a clear 6.1. Photographycomparison could not be made. A problem with

Chitosan has important applications in photo-this spin system is the removal and recovery ofgraphy due to its resistance to abrasion, itslithium from the fibre. The lithium acts as aoptical characteristics, and film forming ability.Lewis acid by solvating the chitin amide group.Silver complexes are not appreciably retainedIt is unclear if this can be completely reversedby chitosan and therefore can easily be pene-through washing, once the fibres are formed.trated from one layer to another of a film bydiffusion [70].5.3.3. Amine oxide /water system

Attempts have been made to develop a pro-6.2. Cosmetics

cess for chitosan fibres by direct dissolutionusing a novel solvent system, N-methylmor- For cosmetic applications, organic acids arepholine oxide /water (NMMO/H O), but no2 usually good solvents, chitin and chitosan haveinteresting tensile data were obtained from these fungicidal and fungistatic properties. Chitosan ispreliminary investigations [69]. the only natural cationic gum that becomes

viscous on being neutralized with acid. Thesematerials are used in creams, lotions and perma-

6. Applications nent waving lotions and several derivatives havealso been reported as nail lacquers [78].

The interest in chitin originates from thestudy of the behaviour and chemical characteris- 6.3. Chitosan as an artificial skintics of lysozyme, an enzyme present in humanbody fluids [70]. A wide variety of medical Individuals who have suffered extensive loss-applications for chitin and chitin derivatives es of skin, commonly in fires, are actually illhave been reported over the last three decades and in danger of succumbing either to massive[71–73]. It has been suggested that chitosan infection or to severe fluid loss. Patients mustmay be used to inhibit fibroplasia in wound often cope with problems of rehabilitation aris-healing and to promote tissue growth and ing from deep, disfiguring scars and cripplingdifferentiation in tissue culture [74]. contractures. Malette et al. studied the effect of

The poor solubility of chitin is the major treatment with chitosan and saline solution onlimiting factor in its utilization. Despite this healing and fibroplasia of wounds made bylimitation, various applications of chitin and scalpel insertions in skin and subcutaneousmodified chitins have been reported, e.g. as raw tissue in the abdominal surface of dogs [79].material for man-made fibres [54]. Fibres made Yannas et al. proposed a design for artificialof chitin and chitosan are useful as absorb- skin, applicable to long-term chronic use, focus-able sutures and wound-dressing materials ing on a nonantigenic membrane, which per-[58,75,76]. Chitin sutures resist attack in bile, forms as a biodegradable template for synthesisurine and pancreatic juice, which are problem of neodermal tissue [80]. It appears thatareas with other absorbable sutures [58]. It has chitosan, having structural characteristics simi-been claimed that wound dressings made of lar to glycosamino glycans, could be consideredchitin and chitosan fibres have applications in for developing such substratum for skin replace-wastewater treatment. Here, the removal of ment [81–83].heavy metal ions by chitosan through chelationhas received much attention [70,77]. Their use 6.3.1. Chitin- and chitosan-based dressingsin the apparal industry, with a much larger Chitin and chitosan have many distinctivescope, could be a long-term possibility [78]. biomedical properties. However, chitin-based


wound healing products are still at the early is accelerated by the oligomers of degradedchitosan by tissue enzymes and this materialstages of research [84].was found to be effective in regenerating theSparkes and Murray [85] developed a sur-skin tissue in the area of the wound.gical dressing made of a chitosan–gelatin com-

Biagini et al. [89] developed an N-carboxy-plex. The procedure involves dissolving thebutyl chitosan dressing for treating plasticchitosan in water in the presence of a suitablesurgery donor sites. A solution of N-carboxy-acid, maintaining the pH of the solution at aboutbutyl chitosan was dialyzed and freeze-dried to2–3, followed by adding the gelatin dissolved in

3produce a 1032030.5 cm soft and flexiblewater. The ratio of chitosan and gelatin is 3:1 topad, which was sterilized and applied to the1:3. To reduce the stiffness of the resultingwound. This dressing could promote ordereddressing a certain amount of plasticizers such astissue regeneration compared to control donorglycerol and sorbitol could be added to thesites. Better histoarchitectural order, better vas-mixture. Dressing film was cast from thiscularization and the absence of inflammatorysolution on a flat plate and dried at roomcells were observed at the dermal level, whiletemperature. It was claimed that, in contrast tofewer aspects of proliferation of the malpighianconventional biological dressings, this ex-layer were reported at the epidermal level.perimental dressing displayed excellent adhe-

The British Textile Technology Groupsion to subcutaneous fat.(BTTG) patented a procedure for making aNara et al. [86] patented a wound dressingchitin-based fibrous dressings [90–93]. In thiscomprising a nonwoven fabric composed ofmethod the chitin /chitosan fibres were not madechitin fibres made by the wet spinning tech-by the traditional fibre-spinning technique andnique. In one of the examples, chitin powderthe raw materials were not from shrimp shellwas ground to 100 mesh and treated in 1 M HClbut from micro-fungi instead. The procedurefor 1 h at 48C. It was then heated to 908C wherecan be summarized as follows.it was treated for 3 h in a 0.3% NaOH solution

to remove calcium and protein in the chitin (i) Micro-fungal mycelia preparation from apowder, and rinsed repeatedly followed by culture of Mucor mucedo growing in adrying. The resultant chitin was dissolved in a nutrient solution.dimethylacetamide solution containing 7 wt% (ii) Culture washing and treatment withlithium chloride to form a 7% dope. After NaOH to remove protein and precipitatefiltering and allowing defoaming to occur, the chitin /chitosan.dope was extruded through a nozzle of diameter (iii) Bleaching and further washing.0.06 mm and 200 holes into butanol at 608C at a (iv) Preparation of the dispersion of fibresrate of 2.2 g/min. The chitin was coagulated using paper-making equipment.and collected at a speed of 10 m/min. The (v) Filtration and wet-laid matt preparation;resultant strand was rinsed with water and dried mixing with other fibres to give mechanicalto obtain a filament of 0.74 dtex with a strength strength.of 2.8 g /den. The filaments were then cut intostaple fibres. Using poly(vinyl alcohol) as a This is a novel method, which uses a non-fibrous binder, nonwoven dressings were made. animal source as the raw material, and the

Kifune et al. [87] developed a new wound resulting micro-fungal fibres are totally differentdressing, Beschitin W, composed of chitin non- from normal spun fibres. They have highlywoven fabric which proved to be beneficial in branched and irregular structures. The fibres areclinical practice. Kim and Min [88] have de- unmanageably brittle when they are allowed toveloped a wound-covering material from poly- dry and a plasticizer has to be associated withelectrolyte complexes of chitosan with sulfon- the whole process and a wet-laid matt is used asated chitosan. It is proposed that wound healing the basic product.


Recently, Muzzarelli [94] introduced another for digestion of milk lactose. Cow’s milk con-tains only a limited amount of the NAG moiety,chitosan derivative, 5-methylpyrrolidinonehence some infants fed cow’s milk may havechitosan, which is believed to be very promisingindigestion. Many animals and some humansin medical applications. This polymer is claimed(including the elderly) have similar lactoseto be compatible with other polymer solutions,intolerances [96,97].including gelatin, poly(vinyl alcohol), poly-

Animal nutritional studies have shown that(vinyl pyrrolidone) and hyaluronic acid. Thethe utilization of whey may be improved if theadvantages include healing of wounded mensi-diet contains small amounts of chitinous materi-cal tissues, and of decubitus ulcers, depressional. This improvement is attributed to the changeof capsule formation around prostheses, limita-in the intestinal microflora brought about by thetion of scar formation and retraction duringchitinous supplement [98]. Chickens fed a com-healing. Some wound-dressing samples weremercial broiler diet containing 20% dried wheyprepared from an aqueous solution of this 5-and 2 or 0.5% chitin had significantly improvedmethylpyrrolidone chitosan, which was dialyzedweight again compared to controls [99,100].and laminated between stainless steel plates andThe feed efficiency ratio shifted from 2.5 tofreeze-dried to yield fleeces. The material could2.38 due to incorporation of chitin in the feedbe fabricated into many different forms, such as[100].filaments, nonwoven fabrics, etc. Once applied

to a wound, 5-methylpyrrolidinone chitosan6.5. Opthalmologybecomes available in the form of oligomers

produced under the action of lysozyme. Chitosan possesses all the characteristics re-Another chitin derivative, dibutyrylchitin, quired for making an ideal contact lens: optical

was prepared by treatment of krill chitin with clarity, mechanical stability, sufficient opticalbutyric anhydride in the presence of perchloric correction, gas permeability, particularly to-acid as a catalyst at 25–308C [95]. Samples of wards oxygen, wettability and immunologicalpolymers with molecular weights high enough compatibility. Contact lenses are made fromto form fibres were obtained and dibutyryl partially depolymerized and purified squid penchitin fibres were made by dry spinning a 20– chitosan by spin casting technology and these22% solution into acetone. The fibres have contact lenses are clear, tough and possess othertensile properties similar to or better than those required physical properties such as modulus,of chitin. Moreover, it was claimed that chitin tensile strength, tear strength, elongation, waterfibres with good tensile properties could be content and oxygen permeability. The anti-obtained by alkaline hydrolysis of dibutyryl microbial and wound healing properties ofchitin fibres without destroying the fibre struc- chitosan along with an excellent film capabilityture. make chitosan suitable for development of

As far as chitin-based commercial wound ocular bandage lenses [101].dressings are concerned, one product

(Beschitin , Unitika) is commercially available 6.6. Water engineeringin Japan, which is a nonwoven fabric manufac-tured from chitin filaments. As environmental protection is becoming an

important global problem, the relevant indus-6.4. Food and nutrition tries pay attention to the development of tech-

nology which does not cause environmentalThe N-acetylglucosamine (NAG) moiety problems.

present in human milk promotes the growth ofbifido bacteria, which block other types of 6.6.1. Metal capture from wastewatermicroorganism and generate the lactase required Nair and Madhavan [102] used chitosan for


the removal of mercury from solutions, and the [110]. Due to its unique molecular structure,adsorption kinetics of mercuric ions by chitosan chitosan has an extremely high affinity for manywere reported by Peniche-covas et al. [103]. classes of dyes, including disperse, direct, reac-The results indicate that the efficiency of ad- tive, acid, vat, sulfur and naphthol dyes. The

21sorption of Hg by chitosan depends upon the rate of diffusion of dyes in chitosan is similar toperiod of treatment, the particle size, initial that in cellulose. Only for basic dyes has

21 chitosan a low affinity. Chitosan is versatile inconcentration of Hg and quantity of chitosan.sorbing metals and surfactants, as well as toJha et al. [104] studied the adsorption of

21 derivatization to attract basic dyes and otherCd on chitosan powder over the concentrationmoieties (e.g., proteins from food processingrange of 1–10 ppm using various particle sizesplants).by adopting a similar procedure as for the

The sorption of dyes by chitosan is exother-removal of mercury.mic, an increase in the temperature leads to anHydroxymethyl chitin and other water-solu-increase in the dye sorption rate, but diminishesble derivatives are useful flocculents for anionictotal sorption capacity [111]. However, thesewaste streams. Chitosan N-benzylsulfonate de-effects are small and normal wastewater tem-rivatives were used as sorbents for removal ofperature variations do not significantly affect themetal ions in an acidic medium by Weltrowskioverall decolorization performance [112]. Also,et al. [105]. The selective adsorption capacitythe wastewater pH may be an important factorfor metal ions of amidoximated chitosan bead-in the sorption of certain dyes onto chitosang-PAN copolymer has been studied by Kang etbecause, at low pH, chitosan’s free aminoal. [106]. These investigations clearly indicategroups are protonated, causing them to attractthat chitosan has a natural selectivity for heavyanionic dyes. Contact time or, inversely, fluxmetal ions and is useful for the treatment of(wastewater flow per unit cross-sectional area)wastewater.affects sorption in a complex manner in a fixedMcKay et al. [107] used chitosan for the

21 21 21 21 bed design reactor system due to contact time,removal of Cu , Hg , Ni and Zn withinbed penetration and boundary layer effects. Atthe temperature range 25–608C at near neutralhigh flux, the diversion of liquid into largerpH. Further adsorption parameters for the re-channels around particles and turbulent flowmoval of these metal ions were reported byoccur. In general, a low flux tends to give moreYang et al. [108]. Maruca et al. [109] usedcomplete contaminant removal.chitosan flakes of 0.4–4 mm for the removal of

For almost all the treatment strategies, aCr(III) from wastewater. The adsorption capaci-major factor which has not yet been adequatelyty increased with a decrease in the size of thecharacterized is the effect of typical wastewaterflakes, which implied that metal ions werecontaminants on decolorization efficiencies. Inpreferably adsorbed on the outer surface oftypical dyeing systems it is well known thatchitosan in the removal of Cr(III) from thecertain additives such as salt and surfactants canwastewater. Pseudo-first-order kinetics are re-either accelerate or retard dye sorption pro-ported.cesses. The extreme variability of textile waste-water must be taken into account in the designof any decolorization system.6.6.2. Colour removal from textile mill

Finally, a factor which significantly increaseseffluentsthe sorption rate is the loading thermodynamics,

6.6.2.1. Sorption of dyes which indicates whether a reaction is favoured.No single decolorization method is likely to As loading increases, the driving forces for

be the optimum for all wastewater streams sorption decrease, leading to an ultimate satura-


tion value beyond which further sorption is not range 2.0–7.0 the dye-binding capacity of chitinpossible. was shown to be stable, while chitosan formed

gels below pH 5.5 and could not be evaluated.6.6.2.2. Dye-binding properties of chitin andchitosan 6.7. Paper finishing

Knorr examined the dye-binding propertiesby weighing 0.5 or 2.0 g chitin or chitosan in Chitosan has been reported to impart wetcentrifuge tubes, adding 20 g of aqueous dye strength to paper [117]. Hydroxymethyl chitinsolution (5 to 49 mg dye/ l) and then shaking and other water-soluble derivatives are usefulthe closed centrifuge tubes for 30 min at 200 end additives in paper making. This polymer,rpm in a horizontal position. The samples were although potentially available in large quan-then centrifuged for 35 min at 45003g, the tities, never became a commercially significantsupernatant decanted and the water uptake of product. The entrepreneur in paper making canchitin and chitosan determined after Sosulski utilize this polymer for better finish paper[113]. The absorbance of the supernatant was properties.measured at 505 nm using decolorized water asa blank. The weight of the supernatant was used 6.8. Solid-state batteriesas the basis for the calculation of the totalamount of dye bound or released. pH adjust- Chitosan is insoluble in water. This poses ament was carried out by using either 10 ml of a problem in the fabrication of solid-state proton-commercial buffer solution or by adding 0.1 M conducting batteries because there will not beHCl to a slurry of 0.5 g chitin /chitosan and 10 any water present in the chitosan which can actml of dye solution. After stirring for 15 min, the as a source of hydrogen ions. In other words,pH was readjusted and deionized water added to the proton-conducting polymer needed for solid-20.5 g total weight. Chitosan formed gels at pH state battery application cannot be obtainedvalues below 5.5 and no dye-binding measure- from chitosan alone. Chitosan is a biopolymerments could be obtained. which can provide ionic conductivity when

The effects of dye concentration and chitin / dissolved in acetic acid. The conductivity is duechitosan dye solution ratios on dye-binding to the presence of protons from the acetic acidcapacity and water uptake of chitin and chitosan solution. The transport of these protons isare discussed in detail elsewhere [114]. Marked thought to occur through many microvoids indifferences between water uptake of chitin and the polymer since the dielectric constants fromchitosan exist with chitosan taking more water piezoelectric studies are small. The choice of athan chitin. The difference may be due to more suitable electrode material may produce adifferences in crystallinity of the products or better battery system [118].due to differences in the amount of salt-forminggroups [115]. Differences in the amount of 6.9. Drug-delivery systemscovalently bound protein residue might alsoaffect water uptake. Controlled-release technology emerged dur-

Dye concentrations had no marked effect on ing the 1980s as a commercially sound meth-the water uptake but correlated significantly odology. The achievement of predictable andwith the dye-binding capacity of chitin and reproducible release of an agent into a specificchitosan [116]. The effect of pH on the dye- environment over an extended period of timebinding capacity of chitin and chitosan was also has much significant merit. It creates a desiredstudied. A decline in the dye-binding capacity environment with optimal response, minimumabove pH 7.0 was observed. Within the pH side-effects and prolonged efficacy. Controlled-


release dosage forms enhance the safety, effica- tion in the stomach [133,134]. Also, chitosanmatrix formulations appear to float and gradual-cy and reliability of drug therapy. They regulately swell in an acid medium. All these interestingthe drug release rate and reduce the frequencyproperties of chitosan make this natural polymerof drug administration to encourage patients toan ideal candidate for controlled drug releasecomply with dosing instructions. Conventionalformulations. Many excellent reviews and booksdosage forms often lead to wide swings indeal with the properties, chemistry, biochemis-serum drug concentrations. Most of the drugtry and applications of chitin, chitosan and theircontent is released soon after administration,derivatives [1,4,54,72,73,75,135,136].causing drug levels in the body to rise rapidly,

peak and then decline sharply. For drugs whose6.9.1. Hydrogels based on chitin and chitosanactions correlate with their serum drug con-

Hydrogels are highly swollen, hydrophiliccentration, the sharp fluctuations often causepolymer networks that can absorb large amountsunacceptable side-effects at the peaks, followedof water and drastically increase in volume. It isby inadequate therapy at the troughs (Fig. 2)well known that the physicochemical properties[119].of the hydrogel depend not only on the molecu-A new dimension is the incorporation oflar structure, the gel structure, and the degree ofbiodegradability into the system. A number ofcrosslinking, but also on the content and state ofdegradable polymers are potentially useful forthe water in the hydrogel. Hydrogels have been

this purpose, including synthetic as well aswidely used in controlled-release systems

natural substances [119–132]. The release of[137,138].

drugs, absorbed or encapsulated by polymers, Recently, hydrogels which swell and contractinvolves their slow and controllable diffusion in response to external pH [139–141] have beenfrom/ through polymeric materials. Production explored. The pH-sensitive hydrogels have po-of slow release (SR) drugs by the pharma- tential use in site-specific delivery of drugs toceutical industry is now a matter of routine. specific regions of the gastrointestinal tract (GI)Drugs covalently attached to biodegradable and have been prepared for low molecularpolymers or dispersed in a polymeric matrix of weight and protein drug delivery [142]. It issuch macromolecules may be released by ero- known that the release of drugs from hydrogelssion /degradation of the polymer. Therapeutic depends on their structure or their chemicalmolecules, complexed by polymers, may also be properties in response to pH [143,144]. Thesereleased from gels by diffusion. polymers, in certain cases, are expected to

Chitosan is non-toxic and easily bioabsorb- reside in the body for a longer period andable [74] with gel-forming ability at low pH. respond to local environmental stimuli to modu-Moreover, chitosan has antacid and antiulcer late drug release [145]. Sometimes the polymersactivities which prevent or weaken drug irrita- used are biodegradable to obtain a desirable

device to control drug release [146]. Thus, to beable to design hydrogels for a particular applica-tion, it is important to know the nature of thesystems in their environmental conditions. Somerecent advances in controlled-release formula-tions using gels of chitin and chitosan arepresented here.

6.9.1.1. Chitosan /polyether interpenetratingpolymer network (IPN) hydrogel

Yao et al. [147] reported a procedure for theFig. 2. Controlled drug delivery versus immediate release. preparation of semi-IPN hydrogel based on


glutaraldehyde-crosslinked chitosan with an in- hydrogels as wound-covering materials and alsoterpenetrating polyether polymer network. The studied the drug release behaviour using silverpH sensitivity, swelling and release kinetics and sulfadiazine as a model drug [152].structural changes of the gel in different pHsolutions were studied [139,140,148,149]. The 6.9.1.3. Hydrogels of poly(ethylene glycol)-co-physicochemical properties of the hydrogel de- poly(lactone) diacrylate macromers and b-pend not only on the molecular structure, the gel chitinstructure and the degree of crosslinking, but also Lee and Kim [153] reported a procedure foron the content and state of the water in the preparing poly(ester–ether–ester) triblock co-hydrogel. Since the inclusion of water signifi- polymers. The synthesis of the triblock copoly-cantly affects the performance of hydrogels, a mers was carried out by bulk polymerizationstudy of the physical state of water in the using low toxic stannous octoate as catalyst orhydrogels is of great importance to understand without catalyst (Fig. 3). Investigations of thethe nature of interactions between absorbed thermal and mechanical properties were carriedwater and polymers. Yao et al. [149] studied the out. Vitamin A, vitamin E and riboflavin weredynamic water absorption characteristics, state used as model drugs [154,155]. However, thereof water, correlation between state of water and were no reports on swelling kinetics and solu-swelling kinetics of chitosan–polyether hydro- bility parameters of the gels.gels by applying techniques such as DSC andsome novel techniques such as positron annihi- 6.9.1.4. Hydrogels of poly(ethylene glycol)lation life-time spectroscopy. macromer /b-chitosan

Yao et al. [140] observed rapid hydrolysis of In their studies on chitosan for biomedicalthe gel with decrease in the ionic strength, i.e. a applications, Lee et al. [156] reported a pro-higher degree of swelling in lower ionic cedure for preparing semi-IPN polymer networkstrength solution [74]. The hydrolysis of the gel hydrogels composed of b-chitosan and poly-can be controlled by the amount of crosslinker (ethylene glycol) diacrylate macromer. Theapplied. The more crosslinker added, the higher hydrogels were prepared by dissolving a mix-the crosslink density of semi-IPNs, which re- ture of PEGM and b-chitosan in aqueous aceticsults in a lower degree of swelling and slowerhydrolysis [140].

Chlorhexidini acetas and Cimetidine wereused as model drugs for drug release studies. Afast swelling of gels results in higher drugrelease at pH ,6 in comparison to that at pH.6 [139,147].

6.9.1.2. Semi-IPN hydrogel polymer networksof b-chitin and poly(ethylene glycol) macromer

Semi-IPN polymer network hydrogels com-posed of b-chitin and poly(ethylene glycol)macromer were synthesized for biomedical ap-plications [150,151]. The thermal and mechani-cal properties of these hydrogels have also beenstudied. The tensile strengths of semi-IPNs inthe swollen state were found to be between 1.35and 2.41 MPa, the highest reported values to Fig. 3. Synthetic scheme of PEGLM or PEGCM/b-chitin semi-date for crosslinked hydrogels. They used these IPNs.


acid. The resulting mixture was then cast to chitosan (lactose /chitosan) and potato starchfilms, followed by subsequent crosslinking with with chitin (potato starch /chitin), and with2,2-dimethoxy-2-phenylacetophenone as non- chitosan (potato starch /chitosan). The disinte-toxic photo initiator by UV irradiation. They gration properties of tablets made from thesestudied the crystallinity and thermal and me- powders, in comparison with those of combinedchanical properties of the gels. powders of lactose with MCC (lactose /MCC)

and potato starch with MCC (potato starch /6.9.1.5. Hydrogels of chitosan /gelatin hybrid MCC) in order to develop new direct-compres-polymer network sion diluents, are also reported [161]. The

Yao et al. [157] reported a novel hydrogel fluidity of combined powders with chitin andbased on crosslinked chitosan/gelatin with a chitosan was greater than that of the powderglutaraldehyde hybrid polymer network. They with crystalline cellulose. The reported hardnessobserved drastic swelling of the gels at acidic of the tablets follows the order: chitosanpH in comparison to basic solutions. tablets.MCC.chitin. In disintegration studies,Levamisole, cimetidine and chloramphenicol tablets containing less than 70% chitin orwere used as model drugs. A pH-dependent chitosan passed the test. Moreover, the ejectionrelease of cimetidine, levamisole and chloram- force of the tablets of lactose /chitin and lac-phenicol from the gel was reported. tose /chitosan was significantly less than that of

lactose /crystalline cellulose tablets [161]. How-6.9.1.6. Chitosan–amine oxide gel ever, no reports are available on controlled drug

Dutta et al. [30–32] prepared an homoge- release formulations using these tablets.neous chitosan–amine oxide gel and studied itsswelling behavior and release characteristics in 6.9.2.2. Chitosan tablets for controlled release:a buffer solution (pH 7.4) at room temperature. anionic–cationic interpolymer complexHomogenous erosion of the matrix and a near Recently, chitosan has gained importance as azero-order release of ampicillin trihydrate were disintegration agent due to its strong ability toobserved. They reported the thermal properties absorb water. It has been observed that chitosanof the chitosan–amine oxide gel in a further contained in tablets at levels below 70% acts asstudy [31]. a disintegration agent [161,162]. Neau et al.

[163] investigated the sustained-release charac-6.9.2. Chitin and chitosan tablets teristics of ethylcellulose tablets containing

Many direct-compression diluents have been theophylline as the model drug. Several equa-reported in the literature, but every diluent has tions were tested to characterize release mecha-some disadvantages [158]. Microcrystalline cel- nisms with respect to the release data. Thelulose (MCC) has been widely used as a tablet investigations reveal that, at high drug loading,diluent in Japan. Chitin and chitosan, because of drug was released by a diffusion mechanismtheir versatility, have been reported to be useful with a rate constant that increased with andiluents in pharmaceutical preparations increase in aqueous solubility. At low drug[159,160]. loading, polymer relaxation also becomes a

component of the release mechanism. However,6.9.2.1. Directly compressed tablets containing its contribution to drug release was less pro-chitin or chitosan in addition to lactose or nounced as drug solubility decreased, becomingpotato starch negligible in the case of theophylline.

Sawayanagi et al. [161] reported the fluidity Recently, Mi et al. [164] have reportedand compressibility of combined powders of alginate as an anionic polyelectrolyte to controllactose with chitin (lactose /chitin), with the swelling and erosion rates of chitosan tablets


in acidic media. Investigations of the drugrelease mechanism of various tablets have beencarried out based on Peppas’s model [165,166]and nuclear magnetic resonance imaging micro-scopy was used to examine the swelling /diffu-sion mechanism of various tablets [164].

6.9.3. Microcapsules /microspheres of chitosanA ‘microcapsule’ is defined as a spherical

Fig. 4. Schematic structure of a chitosan gel microsphere coatedparticle with size varying from 50 nm to 2 mm, with anionic polysaccharide and lipid.containing a core substance. Microspheres are,in a strict sense, spherical empty particles.However, the terms microcapsules and micro- through a polyion complex formation reaction.spheres are often used synonymously. In addi- In the case of lipid-coated microspheres, thetion, some related terms are used as well. For microspheres along with dipalmitoyl phos-example, ‘microbeads’ and ‘beads’ are used phalidyl choline (DPPC) were dispersed inalternatively. Spheres and spherical particles are chloroform. After evaporation of the solvent,also used for a large size and rigid morphology. microspheres were obtained coated with aRecently, Yao et al. [167] highlighted the prepa- DPPC lipid multilayer, which exhibited a transi-ration and properties of microcapsules and tion temperature of a liquid crystal phase atmicrospheres related to chitosan. Due to the 41.48C. The diameter range of the microspheresattractive properties and wider applications of was 250–300 nm with a narrow distribution.chitosan-based microcapsules and microspheres, The stability of the dispersion was improved bya survey of the applications in controlled drug coating (Fig. 5) the microsphere with anionicrelease formulations is appropriate. Moreover, polysaccharide or a lipid multilayer.microcapsule and microsphere forms have an A comparative study on the release of 5-FUedge over other forms in handling and adminis- and its derivatives from a polysaccharide-coatedtration. microsphere MS (CM) was carried out in

physiological saline at 378C. The data indicated6.9.3.1. Crosslinked chitosan microspheres that the 5-FU release rate decreased in thecoated with polysaccharides or lipid order: free 5-FU.carboxymethyl type 5-FU.

The preparation of crosslinked chitosan ester type 5-FU. The results revealed that themicrospheres coated with polysaccharide or coating layers on the microspheres were effec-lipid for intelligent drug delivery systems has tive barriers to 5-FU release.been reported (Fig. 4) [167]. The microspheres Lipid mutilayers with a homogeneous com-were prepared with an inverse emulsion of 5- position generally show a gel–liquid crystalfluorouracil (5-FU) or its derivative solution of transition. When the temperature is raised tohydrochloric acid of chitosan in toluene con- 428C, which is higher than the phase transitiontaining SPAN 80. Chitosan was crosslinked of 41.48C, the amount of 5-FU released in-through Schiff’s salt formation by adding a creased, and the amount of drug deliveredglutaraldehyde solution in toluene. At the same decreased at 378C, which is lower than thetime, the amino derivatives of 5-FU were transition temperature. Due to the improvedimmobilized, obviously resulting in an increase recognition function of polysaccharide chainsin the amount of drug within the microspheres. for animal cell membranes, delivery systemsThe microspheres were coated with anionic from polysaccharide-coated microspheres, MSpolysaccharides (e.g., carboxymethylchitin, etc.) (CM), seem promising.


Moreover, the release rate can be controlled viathe composition of the HPN and the degree ofdeacetylation of chitosan.

6.9.3.3. Chitosan microspheres for controlledrelease of diclofenac sodium

Gohel et al. [169] reported on chitosan micro-spheres containing diclofenac sodium, whichwere prepared by a coacervation phase sepa-ration method. Chitosan and glutaraldehydewere used as coating material and crosslinkingagent, respectively. In vivo studies were per-formed on New Zealand white rabbits. More-over, the microspheres were found to be stableat 458C for 30 days. Student’s ‘t’ test wasperformed for the results of in vitro dissolutiondata for fresh and aged samples (30 days at458C) and no significant difference was foundupon storage.

6.9.3.4. Chitosan–polyethylene oxideFig. 5. Preparation of MS (CM), MS (CML) and MS (CM)polysaccharide. A schematic diagram. nanoparticles as protein carriers

Hydrophilic nanoparticulate carriers have6.9.3.2. Chitosan /gelatin network polymer many potential applications for the administra-microspheres tion of therapeutic molecules. The recently

In their studies on the pharmaceutical appli- developed hydrophobic–hydrophilic carriers re-cations of chitin and chitosan, Yao and co- quire the use of organic solvents for theirworkers [168] reported chitosan /gelatin net- preparation and have a limited protein-loadingwork polymer microspheres for controlled re- capacity [170–173]. To address these limita-lease of cimetidine. The drug-loaded micro- tions, Calvo et al. [174] reported a new ap-spheres were prepared by dissolving chitosan, proach for the preparation of nanoparticlesgelatin (1:1 by weight) and cimetidine in 5% made solely of hydrophilic polymer. The prepa-acetic acid. A certain amount of Tween-80 and ration technique, based on an ionic gelationliquid paraffin at a water-to-oil ratio of 1:10 was process, is extremely mild and involves aadded to the chitosan /gelatin mixture under mixture of two aqueous phases at room tem-agitation at 650 rpm at 308C. A suitable amount perature (Fig. 6). One phase contains theof 25% aqueous glutaraldehyde was added to chitosan (CS) and a diblock copolymer ofthe inverse emulsion and the system maintained ethylene oxide and sodium tripolyphosphatefor 2 h. Finally, the liquid paraffin was vapor- (TPP). The size (200–1000 nm) and zeta po-ized under vacuum to obtain microspheres. tential (between 120 and 160 mV) of the

The drug release studies were performed in nanoparticles can be modulated conventionallyhydrochloric acid solution (pH 1.0) and potas- by varying the CS/PEO-PPO ratio. Further-sium dihydrogen phosphate (pH 7.8) buffer at more, using bovine serum albumin (BSA) as aan ionic strength of 0.1 m/ l. A pH-dependent model protein, it was shown that these newpulsed-release behavior of the hybrid polymer nanoparticles have great protein loading capaci-network (HPN) matrix was observed [168]. ty (entrapment efficiency up to 80% of the


390 000 chitosan at pH 4 (less than 7% losswith regard to the 150 g/ l initial concentration).

Similarly, the encapsulation of various mole-cules [haemoglobin (Hb), bovine serum albumin(BSA) and dextrans with various molecularweights] in calcium alginate beads coated withchitosan has been reported [176,177]. Theirrelease has been compared and the influence ofthe dimensions, the chemical composition andthe molecular weight of the encapsulated ma-terials have been analysed [176]. The ionic

Fig. 6. The preparation of CS nanoparticles. A schematic dia-interactions between alginate and chitosan atgram.different pH are depicted in Fig. 7.

protein) and can provide continuous release of 6.9.3.6. Multiporous beads of chitosanthe entrapped protein for up to 1 week. Several researchers [178,179] have studied

simple coacervation of chitosan in the product-6.9.3.5. Chitosan /calcium alginate beads ion of chitosan beads. In general, chitosan is

The encapsulation process of chitosan and dissolved in aqueous acetic acid or formic acid.calcium alginate as applied to encapsulation of Using a compressed air nozzle, this solution ishaemoglobin was reported by Huguet et al. blown into NaOH, NaOH–methanol, or ethyl-[175]. In the first process, a mixture of haemo- enediamine solution to form coacervate drops.globin and sodium alginate is added dropwise to The drops are then filtered and washed with hota solution of chitosan and the interior of the and cold water successively. Varying the exclu-capsules thus formed in the presence of CaCl is sion rate of the chitosan solution or the nozzle2

hardened. In the second method, the droplets diameter can control the diameter of the drop-were directly pulled off in a chitosan–CaCl lets. The porosity and strength of the beads2

mixture. Both procedures lead to beads con- correspond to the concentration of the chitosan–taining a high concentration of haemoglobin acid solution, the degree of N-deacetylation of(more than 90% of the initial concentration (150 chitosan, and the type and concentration ofg / l) is retained inside the beads) provided the coacervation agents used.chitosan concentration is sufficient. The chitosan beads described above have

The molecular mass of chitosan (245 000 or been applied in various fields, viz. enzymatic390 000 Da) and the pH (2, 4, or 5.4) had only immobilization, chromatographic support, ad-a slight effect on the entrapment of haemo- sorbent of metal ions, or lipoprotein, and cellglobin, the best retention being obtained with cultures. It was confirmed that the porousbeads prepared at pH 5.4. The release of surfaces of the chitosan beads form a good cellhaemoglobin during bead storage in water was culture carrier. Hayashi and Ikada [180] im-found to be dependent on the molecular weight mobilized protease onto porous chitosan beadsof chitosan. The best retention during storage in with a spacer and found that the immobilizedwater was obtained with beads prepared with a protease had higher pH, and thermal storagehigh molecular weight chitosan solution at pH stability, and exhibited higher activity towards2.0. Considering the total loss in haemoglobin the small ester substrate N-benzyl-L-arginineduring bead formation and after 1 month of ethyl ester. In addition, Nishimura et al. [178]storage in water, the best results were obtained investigated the possibilities of using chitosanby preparing the beads in an 8 g/ l solution of beads as a carrier for the cancer chemothera-


higher release rates at pH 1–2 than at pH7.2–7.4. The effect of the amount of drugloaded, the molecular weight of chitosan and thecrosslinking agent on the drug-delivery profileshave been reported [181–183].

6.9.4. Chitosan-based transdermal drugdelivery systems

Thacharodi and Rao [184–186] reported per-meation-controlled transdermal drug deliverysystems (TDS) using chitosan. Studies on pro-pranolol hydrochloride (prop-HCl) delivery sys-tems using various chitosan membranes withdifferent crosslink densities as drug releasecontrolling membranes and chitosan gel as thedrug reservoir have been performed. Thephysicochemical properties of the membraneshave been characterized and the permeabilitycharacteristics of these membranes to bothlipophilic and hydrophilic drugs have beenreported [184,185]. In vitro evaluations of theTDS devices while supported on rabbit pinnaskin were carried out in modified Franz diffu-sion cells [186]. The in vitro drug releaseprofiles showed that all devices released prop-HCl in a reliable, reproducible manner. Thedrug release was significantly reduced whencrosslinked chitosan membranes were used toregulate drug release in the devices. Moreover,the drug release rate was found to depend on thecrosslink density within the membranes. It wasobserved that the device constructed with aFig. 7. Schematic representation of the ionic interactions betweenchitosan membrane with a high crosslink den-alginate and chitosan: (a) pH 5.4; (b) pH 2.0.

sity released the minimum amount of drug. Thisis due to the decreased permeability coefficient

peutic adriamycin. Recently, Sharma et al. of crosslinked membranes resulting from the[181–183] prepared chitosan microbeads for crosslink points.oral sustained delivery of nefedipine, ampicillinand various steroids by adding these drugs to 6.10. Biotechnologychitosan and then entering a simple coacerva-tion process. These coacervate beads can be 6.10.1. Preparation of biotechnologicalhardened by crosslinking with glutaraldehyde or materialsepoxychloropropane to produce microcapsules Chitin has two hydroxyl groups, whilecontaining rotundine [167]. The release profiles chitosan has one amino group and two hydroxylof the drugs from all these chitosan delivery groups in the repeating hexosamide residue.systems were monitored and showed, in general, Chemical modification of these groups and the


regeneration reaction gives rise to various novel lated, and the self-defence function againstbiofunctional macromolecular products having microbial infection was enhanced at the cellularthe original organization or new types of organi- level. On the basis of these results, severalzation. chitin and chitosan dressing materials (discussed

in the foregoing sections) have been developedcommercially for the healing treatment of6.10.2. Cell-stimulating materialshuman and animal wounds.

6.10.2.1. In plantsMainly two kinds of extracellular chitinase 6.10.3. Antibacterial agents

were found in the normal cell suspension cul- The growth of Escherichia coli was inhibitedture of rice (Oryza sativa L. var. japonica cv. in the presence of more than 0.025% chitosan.Koshihikari). In the presence of a chitin oligo- Chitosan also inhibited the growth of Fusarium,saccharide mixture (degree of polymerization Alternaria and Helminthosporium. The cationic2–8), however, the extracellular chitinase activi- amino groups of chitosan probably bind toty increased about three-fold over the control on anionic groups of these microorganisms, re-secreting an additional extracellular new chitin- sulting in growth inhibition [189].ase isoform. These three chitinase isoforms areone group of pathogenesis-related (PR) proteins 6.10.4. Blood anti-coagulants (heparinoids)in plants [187]. Chitin and chitosan sulphates have blood

Soyabeans were coated with a thin layer of anticoagulant and lipoprotein lipase (LPL)-re-depolymerized chitin, carboxymethyl (CM)- leasing activities. Chitin 3,6-sulfate showedchitin and hydroxyethyl (HE)-chitin, and the about two-fold anticoagulant activity and 0.1-seeds were cultured in the field. It was observed fold LPL-releasing activity over those ofthat the seed chitinase increased 1.5–2.0-fold, heparin; the sulfate derivatives might be usablethe seed germination rate increased by 6%, the as heparinoids for artificial blood dialysis [187].pod number increased by 9%, the plant dryweight increased by 8%, and the crop yield also 6.10.5. Anti-throbogenic and haemostaticincreased by 10–12% over the control [188]. materials

Dressing with chitin films, sponges and fibres Chitosan fibres were found to be throm-enhanced chitinase activity in tree-bark tissues bogenic and haemostatic in an in vitro test, andaround wounds up to four-fold over the control. N-hexanoyl and N-octanoyl chitosan fibres wereThe chitin films, which were implanted in or anti-thrombogenic. Chitosan fibres can be usedused to dress the tree-bark tissues, were digested as haemostatic material; N-hexanoyl and N-within 4 to 24 weeks thereafter and were octanoylchitosan fibres are used as anti-throm-assimilated into the wounded bark tissues. The bogenic materials [190].fate of N-acetyl-D-glucosamine in plant tissue isunknown. Phenylalanine ammonia-lyase was 6.11. Chitosan as fat trapperstimulated by treatment with chitin, and ligninformation in the plant increased. As a result, One of the characters in a recent movie, ‘Thewound healing was accelerated [187]. Full Monty’, had a memorable line: ‘‘The less I

eat, the fatter I get.’’ Its a phenomenon that6.10.2.2. In animals plagues many dieters who eat less and lose

Extracellular lysozyme activity was enhanced muscle instead of fat. As a result, their metabo-in in vitro cultures of several mammalian cells lism slows down and it becomes more and moreby treatment with chitin and its derivatives. As a difficult to control weight. Fortunately, it is notresult, connective tissue formation was stimu- too difficult to lose the right stuff, fat, while


improving muscle tone, metabolism and health. Kochi, India, for providing the sample ofMany supplements can help in the fat reduction chitosan. The author is grateful to the Councilprocess, including pyruvate and chitosan. Pyru- of Scientific and Industrial Research (CSIR),vate, found in red apples, some types of cheese, Ministry of Human Resource Developmentand red wine, stimulates fat loss and boosts Groups, Govt. of India, New Delhi, for financialexercise performance. Chitosan attaches itself to assistance to carry out this research. The authorfat in the stomach before it is digested, thus is indebted to the referees for a thoroughtrapping the fat and preventing its absorption by revision of the manuscript.the digestive tract. Fat in turn binds to thechitosan fibre, forming a mass which the bodycannot absorb, and which is eliminated by the Referencesbody. Chitosan fibre differs from other fibres inthat it possesses a positive ionic charge, which [1] R.A.A. Muzzarelli (Ed.), Natural Chelating Polymers, Per-

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A Review of Chitin and Chitosan Applications

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