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A Review of Chitin and Chitosan Applications

A Review of Chitin and Chitosan Applications

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Reactive & Functional Polymers 46 (2000) 1–27 www.elsevier.

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A review of chitin and chitosan applications q
Majeti N.V. Ravi Kumar*
Department 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 as cellulose. It has become of great interest not only as an underutilized resource, but also as a new functional material of high potential in various fields, and recent progress in chitin chemistry is quite noteworthy. The purpose of this review is to take a closer look at chitin and chitosan applications. Based on current research and existing products, some new and futuristic approaches 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; Transdermal devices

1. Introduction Chitin, a naturally abundant mucopolysaccharide, and the supporting material of crustaceans, insects, etc., is well known to consist of 2-acetamido-2-deoxy-b-D-glucose through a b (1 → 4) linkage. Chitin can be degraded by chitinase. Its immunogenicity is exceptionally low, in spite of the presence of nitrogen. It is a highly insoluble material resembling cellulose in its solubility and low chemical reactivity. It may be regarded as cellulose with hydroxyl at
q This paper is dedicated to Professor M.N.V. Prasad, Ph.D., FNIE (New Delhi), DSc. (hc Colombo), School of Life Sciences, University of Hyderabad, Hyderabad, India, who inspired me with his scientific approach, honesty and human warmth. *Post Bag No. 29, Roorkee 247 667, India. Fax: 191-133273560. E-mail address: mnvrkumar@mailcity.com (M.N.V. Ravi Kumar).

position C-2 replaced by an acetamido group. Like cellulose, it functions naturally as a structural polysaccharide. Chitin is a white, hard, inelastic, nitrogenous polysaccharide and the major source of surface pollution in coastal areas. Chitosan is the N-deacetylated derivative of chitin, although this N-deacetylation is almost never complete. A sharp nomenclature with respect to the degree of N-deacetylation has not been defined between chitin and chitosan [1,2]. The structures of cellulose, chitin and chitosan are shown in Fig. 1. Chitin and chitosan are of commercial interest due to their high percentage of nitrogen (6.89%) compared to synthetically substituted cellulose (1.25%). This makes chitin a useful chelating agent [1]. As most of the present-day polymers are synthetic materials, their biocompatibility and biodegradability are much more limited than those of natural polymers such as cellulose,

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

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radability, non-toxicity, adsorption properties, etc. Recently, much attention has been paid to chitosan as a potential polysaccharide resource [5]. Although several efforts have been reported to prepare functional derivatives of chitosan by chemical modifications [6–8], very few attained solubility in general organic solvents [9,10] and some binary solvent systems [11–13]. Chemically modified chitin and chitosan structures resulting in improved solubility in general organic solvents have been reported by many workers [14–23]. The present review is an attempt to discuss the current applications and future prospects of chitin and chitosan.

2. Processing of chitin and chitosan Chitin is easily obtained from crab or shrimp shells and fungal mycelia. In the first case, chitin production is associated with food industries such as shrimp canning. In the second case, the production of chitosan–glucan complexes is associated with fermentation processes, similar to those for the production of citric acid from Aspergillus niger, Mucor rouxii, and Streptomyces, which involves alkali treatment yielding chitosan–glucan complexes. The alkali removes the protein and deacetylates chitin simultaneously. Depending on the alkali concentra-

Fig. 1. Structures of cellulose, chitin and chitosan.

chitin, chitosan and their derivatives. However, these naturally abundant materials also exhibit a limitation in their reactivity and processability [3,4]. In this respect, chitin and chitosan are recommended as suitable functional materials, because these natural polymers have excellent properties such as biocompatibility, biodeg-

Scheme 1.

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

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tion, some soluble glycans are removed [24]. The processing of crustacean shells mainly involves the removal of proteins and the dissolution of calcium carbonate which is present in crab shells in high concentrations. The resulting chitin is deacetylated in 40% sodium hydroxide at 1208C for 1–3 h. This treatment produces 70% deacetylated chitosan (Scheme 1). 3. Economic aspects The production of chitin and chitosan is currently based on crab and shrimp shells discarded by the canning industries in Oregon, Washington, Virginia and Japan and by various finishing fleets in the Antarctic. Several countries possess large unexploited crustacean resources, e.g. Norway, Mexico and Chile [25]. The production of chitosan from crustacean shells obtained as a food industry waste is economically feasible, especially if it includes the recovery of carotenoids. The shells contain considerable quantities of astaxanthin, a carotenoid that has so far not been synthesized, and which is marketed as a fish food additive in aquaculture, especially for salmon. To produce 1 kg of 70% deacetylated chitosan from shrimp shells, 6.3 kg of HCl and 1.8 kg of NaOH are required in addition to nitrogen, process water (0.5 t) and cooling water (0.9 t). Important items for estimating the production cost include transportation, which varies depending on labor and location. In India, the Central Institute of Fisheries Technology, Kerala, initiated research on chitin and chitosan. From their investigation, they found that dry prawn waste contained 23% and dry squilla contained 15% chitin [26]. They have also reported that the chitinous solid waste fraction of the average Indian landing of shell fish ranges from 60 000 to 80 000 tonnes [27,28]. Chitin and chitosan are now produced commercially in India, Japan, Poland, Norway and Australia. The worldwide price of chitosan (in small quantities) is ca. US$7.5 / 10 g (Sigma and Aldrich price list).

4. Properties of chitin and chitosan Most of the naturally occurring polysaccharides, e.g. cellulose, dextran, pectin, alginic acid, agar, agarose and carragenans, are neutral or acidic in nature, whereas chitin and chitosan are examples of highly basic polysaccharides. Their unique properties include polyoxysalt formation, ability to form films, chelate metal ions and optical structural characteristics [29]. Like cellulose, chitin functions naturally as a structural polysaccharide, but differs from cellulose in its properties. Chitin is highly hydrophobic and is insoluble in water and most organic solvents. It is soluble in hexafluoroisopropanol, hexafluoroacetone, chloroalcohols in conjugation with aqueous solutions of mineral acids [24] and dimethylacetamide containing 5% lithium chloride. Chitosan, the deacetylated product of chitin, is soluble in dilute acids such as acetic acid, formic acid, etc. Recently, the gel forming ability of chitosan in N-methylmorpholine N-oxide and its application in controlled drug release formulations has been reported [30–32]. The hydrolysis of chitin with concentrated acids under drastic conditions produces relatively pure D-glucosamine. The nitrogen content of chitin varies from 5 to 8% depending on the extent of deacetylation, whereas the nitrogen in chitosan is mostly in the form of primary aliphatic amino groups. Chitosan, therefore, undergoes reactions typical of amines, of which N-acylation and Schiff reaction are the most important. Chitosan derivatives are easily obtained under mild conditions and can be considered as substituted glucans. N-Acylation with acid anhydrides or acyl halides introduces amido groups at the chitosan nitrogen. Acetic anhydride affords fully acetylated chitins. Linear aliphatic N-acyl groups above propionyl permit rapid acetylation of hydroxyl groups. Higher benzoylated chitin is soluble in benzyl alcohol, dimethylsulfoxide, formic acid and dichloroacetic acid. The Nhexanoyl, N-decanoyl and N-dodecanoyl deriva-

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tives have been obtained in methanesulfonic acid [33,34]. At room temperature, chitosan forms aldimines and ketimines with aldehydes and ketones, respectively. Reaction with ketoacids followed by reaction with sodium borohydride produces glucans carrying proteic and nonproteic amino groups. N-Carboxymethyl chitosan is obtained from glyoxylic acid. Examples of non-proteic amine acid glucans derived from chitosan are the N-carboxybenzyl chitosans obtained from o- and p-phthalaldehydic acids [24,25]. Chitosan and simple aldehydes produce N-alkyl chitosan upon hydrogenation. The presence of the more or less bulky substituent weakens the hydrogen bonds of chitosan; therefore N-alkyl chitosans swell in water in spite of the hydrophobicity of the alkyl chains, but they retain the film forming property of chitosan [1].

the universally accepted non-toxic N-deacetylated derivative of chitin, where chitin is N-deacetylated to such an extent that it becomes soluble in dilute aqueous acetic and formic acids. In chitin, the acetylated units prevail (degree of acetylation typically 0.90). Chitosan is the fully or partially N-deacetylated derivative of chitin with a typical degree of acetylation of less than 0.35. To define this ratio, attempts have been made with many analytical tools [35–44], which include IR spectroscopy, pyrolysis gas chromatography, gel permeation chromatography and UV spectrophotometry, first derivative of UV spectrophotometry, 1 HNMR spectroscopy, 13 C solid state NMR, thermal analysis, various titration schemes, acid hydrolysis and HPLC, separation spectrometry methods and, more recently, near-infrared spectroscopy [45].

4.1. Physical and chemical characterization
The structural details of cellulose, chitin and chitosan are shown in Fig. 1. Cellulose is a homopolymer, while chitin and chitosan are heteropolymers. Neither random nor block orientation is meant to be implied for chitin and chitosan. The properties of chitin and chitosan such as the origin of the material (discussed in the previous section), the degree of N-deacetylation, molecular weight and solvent and solution properties are discussed in brief. Glycol chitin, a partially O-hydroxyethylated chitin, was the first derivative of practical importance; other derivatives and their proposed uses are shown in Table 1.

4.1.2. Molecular weight Chitosan molecular weight distributions have been obtained using HPLC [46]. The weightaverage molecular weight (Mw ) of chitin and chitosan has been determined by light scattering [47]. Viscometry is a simple and rapid method for the determination of molecular weight; the constants a and K in the Mark–Houwink equation have been determined in 0.1 M acetic acid and 0.2 M sodium chloride solution. The intrinsic viscosity is expressed as
[h ] 5 KM a 5 1.81 3 10 23 M 0.93 The charged nature of chitosan in acid solvents and chitosan’s propensity to form aggregation complexes require care when applying these constants. Furthermore, converting chitin into chitosan lowers the molecular weight, changes the degree of deacetylation, and thereby alters the charge distribution, which in turn influences the agglomeration. The weight-average molecular weight of chitin is 1.03310 6 to 2.5310 6 , but the N-deacetylation reaction reduces this to 1310 5 to 5310 5 [48].

4.1.1. Degree of N-acetylation An important parameter to examine closely is the degree of N-acetylation in chitin, i.e. the ratio of 2-acetamido-2-deoxy-D-glucopyranose to 2-amino-2-deoxy-D-glucopyranose structural units. This ratio has a striking effect on chitin solubility and solution properties. Chitosan is

M.N.V. Ravi Kumar / Reactive & Functional Polymers 46 (2000) 1 – 27 Table 1 Chitin derivatives and their proposed uses Derivative N-Acyl chitosans Examples Formyl, acetyl, propionyl, butyryl, hexanoyl, octanoyl, decanoyl, dodecanoyl, tetradecanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, benzoyl, monochloroacetoyl, dichloroacetyl, trifluoroacetyl, carbamoyl, succinyl, acetoxybenzoyl N-Carboxybenzyl, glycine-glucan (N-carboxymethyl chitosan), alanine glucan, phenylalanine glucan, tyrosine glucan, serine glucan, glutamic acid glucan, methionine glucan, leucine glucan From anhydrides such as maleic, itaconic, acetylthiosuccinic, glutaric, cyclohexane 1,2-dicarboxylic, phthalic, cis-tetrahydrophthalic, 5-norbornene-2,3-dicarboxylic, diphenic, salicylic, trimellitic, pyromellitic anhydride o-Carboxymethyl, crosslinked o-carboxymethyl Potential uses Textiles, membranes and medical aids

5

N-Carboxyalkyl (aryl) chitosans

Chromatographic media and metal ion collection ?

N-Carboxyacyl chitosans

o-Carboxyalkyl chitosans

Molecular sieves, viscosity builders, and metal ion collection ?

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-ylchitosans, products obtained from ascorbic acid Palladium, copper, silver, iodine

Metal ion chelates

Catalyst, photography, health products, and insecticides Textiles

Semisynthetic resins of chitosan Natural polysaccharide complexes, miscellaneous

Copolymer of chitosan with methyl methacrylate, polyurea-urethane, poly(amideester), acrylamidemaleic anhydride Chitosan glucans from various organisms Alkyl chitin, benzyl chitin Hydroxy butyl chitin, cyanoethyl chitosan

Hydroxy ethyl glycol chitosan Glutaraldehyde chitosan Linoelic acid–chitosan complex Uracylchitosan, theophylline chitosan, adeninechitosan, chitosan salts of acid polysaccharides, chitosan streptomycin, 2-amido-2,6-diaminoheptanoic acid chitosan

Flocculation and metal ion chelation Intermediate, serine protease purification Desalting filtration, dialysis and insulating papers Enzymology, dialysis and special papers Enzyme immobilization Food additive and anticholesterolemic

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4.1.3. Solvent and solution properties Both cellulose and chitin are highly crystalline, intractable materials and only a limited number of solvents are known which are applicable as reaction solvents. Chitin and chitosan degrade before melting, which is typical for polysaccharides with extensive hydrogen bonding. This makes it necessary to dissolve chitin and chitosan in an appropriate solvent system to impart functionality. For each solvent system, polymer concentration, pH, counterion concentration and temperature effects on the solution viscosity must be known. Comparative data from solvent to solvent are not available. As a general rule, the maximum amount of polymer is dissolved in a given solvent towards a homogeneous solution. Subsequently, the polymer is regenerated in the required form (discussed in the following sections). A coagulant is required for polymer regeneration or solidification. The nature of the coagulant is also highly dependent on the solvent and solution properties as well as the polymer used [54,75].
5. Chitin and its derivatives in fibre formation

5.1. Natural microfibriller arrangement
Chitin has been known to form microfibrillar arrangements in living organisms. These fibrils are usually embedded in a protein matrix and have diameters from 2.5 to 2.8 nm. Crustacean cuticles possess chitin microfibrils with diameters as large as 25 nm. The presence of microfibrils suggests that chitin has characteristics which make it a good candidate for fibre spinning. To spin chitin or chitosan fibres, the raw polymer must be suitably redissolved after removal of extraneous material such as calcium carbonate and proteins, which encase the microfibrils.

5.2. Fibre formation — in retrospection
Numerous methods of spinning chitin fibres have been reported since Von Weimarn reported

the first solutions of chitin that could be formed into a ‘ropy-plastic’ state in 1926. He prepared the solution using inorganic salts capable of strong hydration [49], such as LiCNS, Ca(CNS) 2 , CaI 2 , CaBr 2 , CaCl 2 , etc. After this report, many solvent systems including organic solvents and mixtures of inorganic salts and organic solvents came into existence. To help the dissolution of chitin, it was Ndeacetylated in 5% caustic soda at 608C for 14 days [50]. Another procedure for N-deacetylation was to place the chitin in an autoclave for 3 h at 1808C and 10 atm pressure. It was pointed out that 6 to 10% of solids of N-deacetylated chitin can be brought into acidic solution at room temperature. Aqueous acetic acid was found to be suitable for this purpose. After passing the polymer solutions through a filter press to remove impurities, fibres were spun. Chemicals incompatible with chitin were suggested as coagulants. The resultant fibres were washed and dried under tension. The final product fibres had a round- to heart-shaped cross section with a tensile breaking load of 35 kg / mm 2 (345 Pa). The fibres possessed a dull luster similar to natural silk, leading to the suggestion that the N-deacetylated chitin fibres would make good artificial hair. The collection and recycling of chitin from small-scale consumers was also suggested. Clark and Smith reported a procedure for producing fibres by dissolution of chitin at 958C in presaturated solutions of lithium thiocyanate (saturated 608C) [51]. No tensile properties or solution concentrations were reported. However, X-ray analysis showed a high degree of orientation. Solvent removal was not successful even at 2008C. Lithium iodide was implied to have behaved in the same manner. A ratio of 5 mol lithium thiocyanate per mole anhydroglucose unit was found to exist. This is comparable to the cellulose–lithium thiocyanate compound. Cellulose solubility and the role of solvate / salt complexes have been reviewed in detail [52,53]. Recently, Rathke and Hudson published a review highlighting the ability of chitin and chitosan as fibre and film formers [54].

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5.3. Novel solvent spin systems 5.3.1. Halogenated solvent spin system In 1975, Austin suggested organic solvents containing acids for the direct dissolution of chitin. Such a system was chloroethanol and sulfuric acid. The precipitation of chitin in fibrillar form in water, methanol, or aqueous ammonium hydroxide was mentioned, but no fibre tensile data were presented [55]. In 1975, Brine and Austin suggested trichloroacetic acid (TCA) as a chitin solvent. Chitin was pulverized and two parts by weight were added to 87 parts by weight of a solvent mixture containing 40% TCA, 40% chloral hydrate (US Department of Justice, Drug Enforcement Agency, class IV controlled substance), and 20% methylene chloride over a period of 30–45 min. A filament was extruded from this solution using a hypodermic needle and acetone as the coagulant. The filament was then neutralized with potassium hydroxide (KOH) in 2-propanol followed by washing in deionized water. The filaments were then cold drawn. Two tensile breaks were taken at 60% relative humidity and room temperature. The first was from a filament with a cross section of 0.0830.10 mm, yielding a tensile strength of 72 kg / mm 2 (710 Pa) and a breaking elongation of 13%. The second filament had a cross section of 0.01430.740 mm, indicating a collapsed core structure. It had a tensile strength of 104 kg / mm 2 (1026 Pa) and a breaking elongation of 44% [56]. Syringing a filament cannot be interpreted as conclusive evidence for a possible wet spinning process. While syringe extrusion might indicate the selection of a coagulant, it would be rather surprising to obtain meaningful tensile data. Shear forces in a spinneret are much greater than those experienced in a syringe tip. Kifune and co-workers suggested dissolving chitin in TCA and a chlorinated hydrocarbon such as chloromethane, dichloromethane, and 1,1,2-trichloroethane. The TCA concentration should be kept between 25 and 75%. A concentration range between 1 and 10% chitin was

suggested as well as dissolution below room temperature. Fibres were extruded through a spinneret of 0.04 and 0.06 mm diameter into an acetone coagulation bath followed by a methanol bath. The tensile strength of dried filaments was in the range of 1.67 to 3.1 g / d with an elongation from 8.7 to 20.0%. The strength of the fibres was improved by leaving them in a 0.5 g / l aqueous caustic soda solution for 1 h. The resultant tensile strengths were 2.25 to 3.20 g / d with elongations of 19.2 to 27.3%, respectively [57]. Kifune and co-workers further suggested that these chitin filaments were suitable as absorbable surgical suture [58]. However, TCA is very corrosive and degrades the polymer molecular weight. The breaking elongations suggest that the halogenated solvents act as plasticizers. Fuji Spinning Company dissolved chitosan in a mixture of water and dichloroacetic acid (DCA). The 6.44% chitosan acetate salt solution viscosity was 410 poise. The dope was extruded through a platinum nozzle (30 holes of 0.2 mm diameter each) into basic CuCO 3 –(NH 4 )OH solution to form fibres. Denier and tensile properties were not reported [59]. Tokura and co-workers used a combination of formic acid (FA), DCA and diisopropyl ether as a solvent system. Chitin was cycled several times from 2208C to room temperature in FA, followed by addition of a small amount of DCA. Diisopropyl ether was then added to reduce the solution viscosity to below 199 poise and tensile properties were also reported [60]. It is noteworthy that the wet strength drops to below 0.50 g / d but that the elongation increases to 13%. A TCA / dichloromethane spin system is also described by the Unitika Co. Three parts chitin were dissolved in 50 parts TCA and 50 parts dichloromethane. The defoamed dope was extruded into acetone before wind-up. The bobbins were neutralized with KOH, washed with water, and dried. The fibres had a tensile strength of 2 g / d and 0.5–20 denier [61]. Unitika Co. also used the TCA / chloral hydrate / dichloroethane solvent system for chitin.

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Five parts were dissolved in 100 parts of a 4:4:2 TCA / chloral hydrate / dichloroethane solvent mixture and extruded through a 0.06 mm nozzle into acetone. The fibres were treated with methanolic NaOH. The optimum fibres gave a tenacity of 3.2 g / d with an elongation of 20% [62]. Unitika Co. followed this up with another patent using a 60:40 TCA / trichloroethylene spin dope mixture. Tensile properties were unavailable [63]. In 1983, Unitika Co. showed that a dope consisting of three parts chitin, 50 parts TCA, and 50 parts dichloromethane could be spun at a rate of 1.7 ml / min under 25 kg / cm 2 pressure into acetone to form filaments. The extrusion die had holes of 0.07 mm diameter, indicating a jet velocity of 8.8 m / min and a take-up of 5 m / min. The coagulation bath was maintained at 188C. The filaments were washed with acetone at 188C for 10 min, rewound at 4.5 m / min, then neutralized, washed and dried. The multifilament product had a total denier of 150 with a tenacity of 2.65 g / d [63]. A similar system using four parts chitin in the same solvent but a 40-hole die of 0.08 mm diameter each was also used. The jet velocity was 10.4 m / min into a 258C acetone bath. A rewinding at 7 m / min followed the first take-up roll at 5 m / min. The total denier was 175; however, no tensile properties were reported [64]. Some of the halogenated solvent systems attained dry tenacities of above 3 g / d; however, the low wet tenacities were still undesirable. Although the fibre characterization was much better for these systems, the polymer characterization lacked molecular weight as well as degree of N-acetylation formation. Solution properties would be hard to obtain due to rapid chitin degradation in these solvents. Although anhydrous coagulation baths were used and compared, fibres were neutralized in aqueous media. A study in completely anhydrous systems would be of interest, since it may lead to more densely consolidated fibres. The implementation of these spin systems represents a problem due to the nature of the solvents. TCA and DCA are corrosive and degrade the polymer

upon short exposures. Chlorohydrocarbons are increasingly environmentally unacceptable solvents. Hexafluoro-2-propanol and hexafluoroacetone sesquihydrate are toxic. Formic acid can act as a sensitizer.

5.3.2. Amide–LiCl system In 1978, Rutherford and Austin summarized the problems encountered in finding a solvent system for chitin [65]. Austin suggested N,Ndimethylacetamide (DMAc)–5% LiCl or Nmethyl-2-pyrrolidone (NMP)–5% LiCl as solvents for chitin. A solution of 5% w / v was obtained within 2 h with these systems. A filament was extruded from the solution using a 15-gauge needle into an acetone coagulation bath. This was followed by more washing and drawing in acetone. The final filament was washed in deionized water. Tensile properties were obtained at 60% R.H. and room temperature at an applied stress of 0.1 cm / min. The resultant dry tensile strengths for different crab and shrimp species ranged from 24 to 60 kg / mm 2 (236–592 Pa) [66]. Russian researchers spun chitin fibres out of DMAc / NMP solutions containing 5% chitin and 5% LiCl (based on chitin content). These fibres were drawn in a 50:50 ethanol / ethylene glycol bath, giving an average yield strength of 390 MPa with 3% elongation. An initial modulus of 2 GPa was also reported. Scanning electron microscopy showed fibres with a round fibrillar cross section [67]. A follow-up study showed a decrease in the elasticity modulus and relative elongation with increase in the degree of N-acetylation (12–30%). From X-ray analysis, an increase in the amount of amorphous regions was observed with increase in degree of acetylation [68]. The amide–lithium systems showed some of the best dry tenacities, although they still lack adequate wet tenacities. The low wet tenacities are probably due to low crystallinity and poor consolidation of the fibre. The fibres and spin dopes were well characterized but the polymers used to prepare these dopes were not. Some

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coagulation studies were carried out but a clear comparison could not be made. A problem with this spin system is the removal and recovery of lithium from the fibre. The lithium acts as a Lewis acid by solvating the chitin amide group. It is unclear if this can be completely reversed through washing, once the fibres are formed.

6.1. Photography
Chitosan has important applications in photography due to its resistance to abrasion, its optical characteristics, and film forming ability. Silver complexes are not appreciably retained by chitosan and therefore can easily be penetrated from one layer to another of a film by diffusion [70].

5.3.3. Amine oxide /water system Attempts have been made to develop a process for chitosan fibres by direct dissolution using a novel solvent system, N-methylmorpholine oxide / water (NMMO / H 2 O), but no interesting tensile data were obtained from these preliminary investigations [69].

6.2. Cosmetics
For cosmetic applications, organic acids are usually good solvents, chitin and chitosan have fungicidal and fungistatic properties. Chitosan is the only natural cationic gum that becomes viscous on being neutralized with acid. These materials are used in creams, lotions and permanent waving lotions and several derivatives have also been reported as nail lacquers [78].

6. Applications The interest in chitin originates from the study of the behaviour and chemical characteristics of lysozyme, an enzyme present in human body fluids [70]. A wide variety of medical applications for chitin and chitin derivatives have been reported over the last three decades [71–73]. It has been suggested that chitosan may be used to inhibit fibroplasia in wound healing and to promote tissue growth and differentiation in tissue culture [74]. The poor solubility of chitin is the major limiting factor in its utilization. Despite this limitation, various applications of chitin and modified chitins have been reported, e.g. as raw material for man-made fibres [54]. Fibres made of chitin and chitosan are useful as absorbable sutures and wound-dressing materials [58,75,76]. Chitin sutures resist attack in bile, urine and pancreatic juice, which are problem areas with other absorbable sutures [58]. It has been claimed that wound dressings made of chitin and chitosan fibres have applications in wastewater treatment. Here, the removal of heavy metal ions by chitosan through chelation has received much attention [70,77]. Their use in the apparal industry, with a much larger scope, could be a long-term possibility [78].

6.3. Chitosan as an artificial skin
Individuals who have suffered extensive losses of skin, commonly in fires, are actually ill and in danger of succumbing either to massive infection or to severe fluid loss. Patients must often cope with problems of rehabilitation arising from deep, disfiguring scars and crippling contractures. Malette et al. studied the effect of treatment with chitosan and saline solution on healing and fibroplasia of wounds made by scalpel insertions in skin and subcutaneous tissue in the abdominal surface of dogs [79]. Yannas et al. proposed a design for artificial skin, applicable to long-term chronic use, focusing on a nonantigenic membrane, which performs as a biodegradable template for synthesis of neodermal tissue [80]. It appears that chitosan, having structural characteristics similar to glycosamino glycans, could be considered for developing such substratum for skin replacement [81–83].

6.3.1. Chitin- and chitosan-based dressings Chitin and chitosan have many distinctive biomedical properties. However, chitin-based

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wound healing products are still at the early stages of research [84]. Sparkes and Murray [85] developed a surgical dressing made of a chitosan–gelatin complex. The procedure involves dissolving the chitosan in water in the presence of a suitable acid, maintaining the pH of the solution at about 2–3, followed by adding the gelatin dissolved in water. The ratio of chitosan and gelatin is 3:1 to 1:3. To reduce the stiffness of the resulting dressing a certain amount of plasticizers such as glycerol and sorbitol could be added to the mixture. Dressing film was cast from this solution on a flat plate and dried at room temperature. It was claimed that, in contrast to conventional biological dressings, this experimental dressing displayed excellent adhesion to subcutaneous fat. Nara et al. [86] patented a wound dressing comprising a nonwoven fabric composed of chitin fibres made by the wet spinning technique. In one of the examples, chitin powder was ground to 100 mesh and treated in 1 M HCl for 1 h at 48C. It was then heated to 908C where it was treated for 3 h in a 0.3% NaOH solution to remove calcium and protein in the chitin powder, and rinsed repeatedly followed by drying. The resultant chitin was dissolved in a dimethylacetamide solution containing 7 wt% lithium chloride to form a 7% dope. After filtering and allowing defoaming to occur, the dope was extruded through a nozzle of diameter 0.06 mm and 200 holes into butanol at 608C at a rate of 2.2 g / min. The chitin was coagulated and collected at a speed of 10 m / min. The resultant strand was rinsed with water and dried to obtain a filament of 0.74 dtex with a strength of 2.8 g / den. The filaments were then cut into staple fibres. Using poly(vinyl alcohol) as a fibrous binder, nonwoven dressings were made. Kifune et al. [87] developed a new wound dressing, Beschitin W, composed of chitin nonwoven fabric which proved to be beneficial in clinical practice. Kim and Min [88] have developed a wound-covering material from polyelectrolyte complexes of chitosan with sulfonated chitosan. It is proposed that wound healing

is accelerated by the oligomers of degraded chitosan by tissue enzymes and this material was found to be effective in regenerating the skin tissue in the area of the wound. Biagini et al. [89] developed an N-carboxybutyl chitosan dressing for treating plastic surgery donor sites. A solution of N-carboxybutyl chitosan was dialyzed and freeze-dried to produce a 1032030.5 cm 3 soft and flexible pad, which was sterilized and applied to the wound. This dressing could promote ordered tissue regeneration compared to control donor sites. Better histoarchitectural order, better vascularization and the absence of inflammatory cells were observed at the dermal level, while fewer aspects of proliferation of the malpighian layer were reported at the epidermal level. The British Textile Technology Group (BTTG) patented a procedure for making a chitin-based fibrous dressings [90–93]. In this method the chitin / chitosan fibres were not made by the traditional fibre-spinning technique and the raw materials were not from shrimp shell but from micro-fungi instead. The procedure can be summarized as follows. (i) Micro-fungal mycelia preparation from a culture of Mucor mucedo growing in a nutrient solution. (ii) Culture washing and treatment with NaOH to remove protein and precipitate chitin / chitosan. (iii) Bleaching and further washing. (iv) Preparation of the dispersion of fibres using paper-making equipment. (v) Filtration and wet-laid matt preparation; mixing with other fibres to give mechanical strength. This is a novel method, which uses a nonanimal source as the raw material, and the resulting micro-fungal fibres are totally different from normal spun fibres. They have highly branched and irregular structures. The fibres are unmanageably brittle when they are allowed to dry and a plasticizer has to be associated with the whole process and a wet-laid matt is used as the basic product.

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Recently, Muzzarelli [94] introduced another chitosan derivative, 5-methylpyrrolidinone chitosan, which is believed to be very promising in medical applications. This polymer is claimed to be compatible with other polymer solutions, including gelatin, poly(vinyl alcohol), poly(vinyl pyrrolidone) and hyaluronic acid. The advantages include healing of wounded mensical tissues, and of decubitus ulcers, depression of capsule formation around prostheses, limitation of scar formation and retraction during healing. Some wound-dressing samples were prepared from an aqueous solution of this 5methylpyrrolidone chitosan, which was dialyzed and laminated between stainless steel plates and freeze-dried to yield fleeces. The material could be fabricated into many different forms, such as filaments, nonwoven fabrics, etc. Once applied to a wound, 5-methylpyrrolidinone chitosan becomes available in the form of oligomers produced under the action of lysozyme. Another chitin derivative, dibutyrylchitin, was prepared by treatment of krill chitin with butyric anhydride in the presence of perchloric acid as a catalyst at 25–308C [95]. Samples of polymers with molecular weights high enough to form fibres were obtained and dibutyryl chitin fibres were made by dry spinning a 20– 22% solution into acetone. The fibres have tensile properties similar to or better than those of chitin. Moreover, it was claimed that chitin fibres with good tensile properties could be obtained by alkaline hydrolysis of dibutyryl chitin fibres without destroying the fibre structure. As far as chitin-based commercial wound dressings are concerned, one product (Beschitin ® , Unitika) is commercially available in Japan, which is a nonwoven fabric manufactured from chitin filaments.

for digestion of milk lactose. Cow’s milk contains only a limited amount of the NAG moiety, hence some infants fed cow’s milk may have indigestion. Many animals and some humans (including the elderly) have similar lactose intolerances [96,97]. Animal nutritional studies have shown that the utilization of whey may be improved if the diet contains small amounts of chitinous material. This improvement is attributed to the change in the intestinal microflora brought about by the chitinous supplement [98]. Chickens fed a commercial broiler diet containing 20% dried whey and 2 or 0.5% chitin had significantly improved weight again compared to controls [99,100]. The feed efficiency ratio shifted from 2.5 to 2.38 due to incorporation of chitin in the feed [100].

6.5. Opthalmology
Chitosan possesses all the characteristics required for making an ideal contact lens: optical clarity, mechanical stability, sufficient optical correction, gas permeability, particularly towards oxygen, wettability and immunological compatibility. Contact lenses are made from partially depolymerized and purified squid pen chitosan by spin casting technology and these contact lenses are clear, tough and possess other required physical properties such as modulus, tensile strength, tear strength, elongation, water content and oxygen permeability. The antimicrobial and wound healing properties of chitosan along with an excellent film capability make chitosan suitable for development of ocular bandage lenses [101].

6.6. Water engineering
As environmental protection is becoming an important global problem, the relevant industries pay attention to the development of technology which does not cause environmental problems.

6.4. Food and nutrition
The N-acetylglucosamine (NAG) moiety present in human milk promotes the growth of bifido bacteria, which block other types of microorganism and generate the lactase required

6.6.1. Metal capture from wastewater Nair and Madhavan [102] used chitosan for

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the removal of mercury from solutions, and the adsorption kinetics of mercuric ions by chitosan were reported by Peniche-covas et al. [103]. The results indicate that the efficiency of adsorption of Hg 21 by chitosan depends upon the period of treatment, the particle size, initial concentration of Hg 21 and quantity of chitosan. Jha et al. [104] studied the adsorption of Cd 21 on chitosan powder over the concentration range of 1–10 ppm using various particle sizes by adopting a similar procedure as for the removal of mercury. Hydroxymethyl chitin and other water-soluble derivatives are useful flocculents for anionic waste streams. Chitosan N-benzylsulfonate derivatives were used as sorbents for removal of metal ions in an acidic medium by Weltrowski et al. [105]. The selective adsorption capacity for metal ions of amidoximated chitosan beadg-PAN copolymer has been studied by Kang et al. [106]. These investigations clearly indicate that chitosan has a natural selectivity for heavy metal ions and is useful for the treatment of wastewater. McKay et al. [107] used chitosan for the 21 21 21 21 removal of Cu , Hg , Ni and Zn within the temperature range 25–608C at near neutral pH. Further adsorption parameters for the removal of these metal ions were reported by Yang et al. [108]. Maruca et al. [109] used chitosan flakes of 0.4–4 mm for the removal of Cr(III) from wastewater. The adsorption capacity increased with a decrease in the size of the flakes, which implied that metal ions were preferably adsorbed on the outer surface of chitosan in the removal of Cr(III) from the wastewater. Pseudo-first-order kinetics are reported.

6.6.2. Colour removal from textile mill effluents 6.6.2.1. Sorption of dyes No single decolorization method is likely to be the optimum for all wastewater streams

[110]. Due to its unique molecular structure, chitosan has an extremely high affinity for many classes of dyes, including disperse, direct, reactive, acid, vat, sulfur and naphthol dyes. The rate of diffusion of dyes in chitosan is similar to that in cellulose. Only for basic dyes has chitosan a low affinity. Chitosan is versatile in sorbing metals and surfactants, as well as to derivatization to attract basic dyes and other moieties (e.g., proteins from food processing plants). The sorption of dyes by chitosan is exothermic, an increase in the temperature leads to an increase in the dye sorption rate, but diminishes total sorption capacity [111]. However, these effects are small and normal wastewater temperature variations do not significantly affect the overall decolorization performance [112]. Also, the wastewater pH may be an important factor in the sorption of certain dyes onto chitosan because, at low pH, chitosan’s free amino groups are protonated, causing them to attract anionic dyes. Contact time or, inversely, flux (wastewater flow per unit cross-sectional area) affects sorption in a complex manner in a fixed bed design reactor system due to contact time, bed penetration and boundary layer effects. At high flux, the diversion of liquid into larger channels around particles and turbulent flow occur. In general, a low flux tends to give more complete contaminant removal. For almost all the treatment strategies, a major factor which has not yet been adequately characterized is the effect of typical wastewater contaminants on decolorization efficiencies. In typical dyeing systems it is well known that certain additives such as salt and surfactants can either accelerate or retard dye sorption processes. The extreme variability of textile wastewater must be taken into account in the design of any decolorization system. Finally, a factor which significantly increases the sorption rate is the loading thermodynamics, which indicates whether a reaction is favoured. As loading increases, the driving forces for sorption decrease, leading to an ultimate satura-

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tion value beyond which further sorption is not possible.

range 2.0–7.0 the dye-binding capacity of chitin 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 and chitosan Knorr examined the dye-binding properties by weighing 0.5 or 2.0 g chitin or chitosan in centrifuge tubes, adding 20 g of aqueous dye solution (5 to 49 mg dye / l) and then shaking the closed centrifuge tubes for 30 min at 200 rpm in a horizontal position. The samples were then centrifuged for 35 min at 45003g, the supernatant decanted and the water uptake of chitin and chitosan determined after Sosulski [113]. The absorbance of the supernatant was measured at 505 nm using decolorized water as a blank. The weight of the supernatant was used as the basis for the calculation of the total amount of dye bound or released. pH adjustment was carried out by using either 10 ml of a commercial buffer solution or by adding 0.1 M HCl to a slurry of 0.5 g chitin / chitosan and 10 ml of dye solution. After stirring for 15 min, the pH was readjusted and deionized water added to 20.5 g total weight. Chitosan formed gels at pH values below 5.5 and no dye-binding measurements could be obtained. The effects of dye concentration and chitin / chitosan dye solution ratios on dye-binding capacity and water uptake of chitin and chitosan are discussed in detail elsewhere [114]. Marked differences between water uptake of chitin and chitosan exist with chitosan taking more water than chitin. The difference may be due to differences in crystallinity of the products or due to differences in the amount of salt-forming groups [115]. Differences in the amount of covalently bound protein residue might also affect water uptake. Dye concentrations had no marked effect on the water uptake but correlated significantly with the dye-binding capacity of chitin and chitosan [116]. The effect of pH on the dyebinding capacity of chitin and chitosan was also studied. A decline in the dye-binding capacity above pH 7.0 was observed. Within the pH

6.7. Paper finishing
Chitosan has been reported to impart wet strength to paper [117]. Hydroxymethyl chitin and other water-soluble derivatives are useful end additives in paper making. This polymer, although potentially available in large quantities, never became a commercially significant product. The entrepreneur in paper making can utilize this polymer for better finish paper properties.

6.8. Solid-state batteries
Chitosan is insoluble in water. This poses a problem in the fabrication of solid-state protonconducting batteries because there will not be any water present in the chitosan which can act as a source of hydrogen ions. In other words, the proton-conducting polymer needed for solidstate battery application cannot be obtained from chitosan alone. Chitosan is a biopolymer which can provide ionic conductivity when dissolved in acetic acid. The conductivity is due to the presence of protons from the acetic acid solution. The transport of these protons is thought to occur through many microvoids in the polymer since the dielectric constants from piezoelectric studies are small. The choice of a more suitable electrode material may produce a better battery system [118].

6.9. Drug-delivery systems
Controlled-release technology emerged during the 1980s as a commercially sound methodology. The achievement of predictable and reproducible release of an agent into a specific environment over an extended period of time has much significant merit. It creates a desired environment with optimal response, minimum side-effects and prolonged efficacy. Controlled-

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release dosage forms enhance the safety, efficacy and reliability of drug therapy. They regulate the drug release rate and reduce the frequency of drug administration to encourage patients to comply with dosing instructions. Conventional dosage forms often lead to wide swings in serum drug concentrations. Most of the drug content is released soon after administration, causing drug levels in the body to rise rapidly, peak and then decline sharply. For drugs whose actions correlate with their serum drug concentration, the sharp fluctuations often cause unacceptable side-effects at the peaks, followed by inadequate therapy at the troughs (Fig. 2) [119]. A new dimension is the incorporation of biodegradability into the system. A number of degradable polymers are potentially useful for this purpose, including synthetic as well as natural substances [119–132]. The release of drugs, absorbed or encapsulated by polymers, involves their slow and controllable diffusion from / through polymeric materials. Production of slow release (SR) drugs by the pharmaceutical industry is now a matter of routine. Drugs covalently attached to biodegradable polymers or dispersed in a polymeric matrix of such macromolecules may be released by erosion / degradation of the polymer. Therapeutic molecules, complexed by polymers, may also be released from gels by diffusion. Chitosan is non-toxic and easily bioabsorbable [74] with gel-forming ability at low pH. Moreover, chitosan has antacid and antiulcer activities which prevent or weaken drug irrita-

tion in the stomach [133,134]. Also, chitosan matrix formulations appear to float and gradually swell in an acid medium. All these interesting properties of chitosan make this natural polymer an ideal candidate for controlled drug release formulations. Many excellent reviews and books deal with the properties, chemistry, biochemistry and applications of chitin, chitosan and their derivatives [1,4,54,72,73,75,135,136].

6.9.1. Hydrogels based on chitin and chitosan Hydrogels are highly swollen, hydrophilic polymer networks that can absorb large amounts of water and drastically increase in volume. It is well known that the physicochemical properties of the hydrogel depend not only on the molecular structure, the gel structure, and the degree of crosslinking, but also on the content and state of the water in the hydrogel. Hydrogels have been widely used in controlled-release systems [137,138]. Recently, hydrogels which swell and contract in response to external pH [139–141] have been explored. The pH-sensitive hydrogels have potential use in site-specific delivery of drugs to specific regions of the gastrointestinal tract (GI) and have been prepared for low molecular weight and protein drug delivery [142]. It is known that the release of drugs from hydrogels depends on their structure or their chemical properties in response to pH [143,144]. These polymers, in certain cases, are expected to reside in the body for a longer period and respond to local environmental stimuli to modulate drug release [145]. Sometimes the polymers used are biodegradable to obtain a desirable device to control drug release [146]. Thus, to be able to design hydrogels for a particular application, it is important to know the nature of the systems in their environmental conditions. Some recent advances in controlled-release formulations using gels of chitin and chitosan are presented here. 6.9.1.1. Chitosan /polyether interpenetrating polymer network ( IPN) hydrogel Yao et al. [147] reported a procedure for the preparation of semi-IPN hydrogel based on

Fig. 2. Controlled drug delivery versus immediate release.

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glutaraldehyde-crosslinked chitosan with an interpenetrating polyether polymer network. The pH sensitivity, swelling and release kinetics and structural changes of the gel in different pH solutions were studied [139,140,148,149]. The physicochemical properties of the hydrogel depend not only on the molecular structure, the gel structure and the degree of crosslinking, but also on the content and state of the water in the hydrogel. Since the inclusion of water significantly affects the performance of hydrogels, a study of the physical state of water in the hydrogels is of great importance to understand the nature of interactions between absorbed water and polymers. Yao et al. [149] studied the dynamic water absorption characteristics, state of water, correlation between state of water and swelling kinetics of chitosan–polyether hydrogels by applying techniques such as DSC and some novel techniques such as positron annihilation life-time spectroscopy. Yao et al. [140] observed rapid hydrolysis of the gel with decrease in the ionic strength, i.e. a higher degree of swelling in lower ionic strength solution [74]. The hydrolysis of the gel can be controlled by the amount of crosslinker applied. The more crosslinker added, the higher the crosslink density of semi-IPNs, which results in a lower degree of swelling and slower hydrolysis [140]. Chlorhexidini acetas and Cimetidine were used as model drugs for drug release studies. A fast swelling of gels results in higher drug release at pH ,6 in comparison to that at pH .6 [139,147].

hydrogels as wound-covering materials and also studied the drug release behaviour using silver sulfadiazine as a model drug [152].

6.9.1.3. Hydrogels of poly(ethylene glycol)-copoly( lactone) diacrylate macromers and b chitin Lee and Kim [153] reported a procedure for preparing poly(ester–ether–ester) triblock copolymers. The synthesis of the triblock copolymers was carried out by bulk polymerization using low toxic stannous octoate as catalyst or without catalyst (Fig. 3). Investigations of the thermal and mechanical properties were carried out. Vitamin A, vitamin E and riboflavin were used as model drugs [154,155]. However, there were no reports on swelling kinetics and solubility parameters of the gels. 6.9.1.4. Hydrogels of poly(ethylene glycol) macromer /b -chitosan In their studies on chitosan for biomedical applications, Lee et al. [156] reported a procedure for preparing semi-IPN polymer network hydrogels composed of b-chitosan and poly(ethylene glycol) diacrylate macromer. The hydrogels were prepared by dissolving a mixture of PEGM and b-chitosan in aqueous acetic

6.9.1.2. Semi-IPN hydrogel polymer networks of b -chitin and poly(ethylene glycol) macromer Semi-IPN polymer network hydrogels composed of b-chitin and poly(ethylene glycol) macromer were synthesized for biomedical applications [150,151]. The thermal and mechanical properties of these hydrogels have also been studied. The tensile strengths of semi-IPNs in the swollen state were found to be between 1.35 and 2.41 MPa, the highest reported values to date for crosslinked hydrogels. They used these

Fig. 3. Synthetic scheme of PEGLM or PEGCM / b-chitin semiIPNs.

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acid. The resulting mixture was then cast to films, followed by subsequent crosslinking with 2,2-dimethoxy-2-phenylacetophenone as nontoxic photo initiator by UV irradiation. They studied the crystallinity and thermal and mechanical properties of the gels.

6.9.1.5. Hydrogels of chitosan /gelatin hybrid polymer network Yao et al. [157] reported a novel hydrogel based on crosslinked chitosan / gelatin with a glutaraldehyde hybrid polymer network. They observed drastic swelling of the gels at acidic pH in comparison to basic solutions. Levamisole, cimetidine and chloramphenicol were used as model drugs. A pH-dependent release of cimetidine, levamisole and chloramphenicol from the gel was reported. 6.9.1.6. Chitosan–amine oxide gel Dutta et al. [30–32] prepared an homogeneous chitosan–amine oxide gel and studied its swelling behavior and release characteristics in a buffer solution (pH 7.4) at room temperature. Homogenous erosion of the matrix and a near zero-order release of ampicillin trihydrate were observed. They reported the thermal properties of the chitosan–amine oxide gel in a further study [31]. 6.9.2. Chitin and chitosan tablets Many direct-compression diluents have been reported in the literature, but every diluent has some disadvantages [158]. Microcrystalline cellulose (MCC) has been widely used as a tablet diluent in Japan. Chitin and chitosan, because of their versatility, have been reported to be useful diluents in pharmaceutical preparations [159,160]. 6.9.2.1. Directly compressed tablets containing chitin or chitosan in addition to lactose or potato starch Sawayanagi et al. [161] reported the fluidity and compressibility of combined powders of lactose with chitin (lactose / chitin), with

chitosan (lactose / chitosan) and potato starch with chitin (potato starch / chitin), and with chitosan (potato starch / chitosan). The disintegration properties of tablets made from these powders, in comparison with those of combined powders of lactose with MCC (lactose / MCC) and potato starch with MCC (potato starch / MCC) in order to develop new direct-compression diluents, are also reported [161]. The fluidity of combined powders with chitin and chitosan was greater than that of the powder with crystalline cellulose. The reported hardness of the tablets follows the order: chitosan tablets.MCC.chitin. In disintegration studies, tablets containing less than 70% chitin or chitosan passed the test. Moreover, the ejection force of the tablets of lactose / chitin and lactose / chitosan was significantly less than that of lactose / crystalline cellulose tablets [161]. However, no reports are available on controlled drug release formulations using these tablets.

6.9.2.2. Chitosan tablets for controlled release: anionic–cationic interpolymer complex Recently, chitosan has gained importance as a disintegration agent due to its strong ability to absorb water. It has been observed that chitosan contained in tablets at levels below 70% acts as a disintegration agent [161,162]. Neau et al. [163] investigated the sustained-release characteristics of ethylcellulose tablets containing theophylline as the model drug. Several equations were tested to characterize release mechanisms with respect to the release data. The investigations reveal that, at high drug loading, drug was released by a diffusion mechanism with a rate constant that increased with an increase in aqueous solubility. At low drug loading, polymer relaxation also becomes a component of the release mechanism. However, its contribution to drug release was less pronounced as drug solubility decreased, becoming negligible in the case of theophylline. Recently, Mi et al. [164] have reported alginate as an anionic polyelectrolyte to control the swelling and erosion rates of chitosan tablets

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in acidic media. Investigations of the drug release mechanism of various tablets have been carried out based on Peppas’s model [165,166] and nuclear magnetic resonance imaging microscopy was used to examine the swelling / diffusion mechanism of various tablets [164].

6.9.3. Microcapsules /microspheres of chitosan A ‘microcapsule’ is defined as a spherical particle with size varying from 50 nm to 2 mm, containing a core substance. Microspheres are, in a strict sense, spherical empty particles. However, the terms microcapsules and microspheres are often used synonymously. In addition, some related terms are used as well. For example, ‘microbeads’ and ‘beads’ are used alternatively. Spheres and spherical particles are also used for a large size and rigid morphology. Recently, Yao et al. [167] highlighted the preparation and properties of microcapsules and microspheres related to chitosan. Due to the attractive properties and wider applications of chitosan-based microcapsules and microspheres, a survey of the applications in controlled drug release formulations is appropriate. Moreover, microcapsule and microsphere forms have an edge over other forms in handling and administration. 6.9.3.1. Crosslinked chitosan microspheres coated with polysaccharides or lipid The preparation of crosslinked chitosan microspheres coated with polysaccharide or lipid for intelligent drug delivery systems has been reported (Fig. 4) [167]. The microspheres were prepared with an inverse emulsion of 5fluorouracil (5-FU) or its derivative solution of hydrochloric acid of chitosan in toluene containing SPAN 80. Chitosan was crosslinked through Schiff’s salt formation by adding a glutaraldehyde solution in toluene. At the same time, the amino derivatives of 5-FU were immobilized, obviously resulting in an increase in the amount of drug within the microspheres. The microspheres were coated with anionic polysaccharides (e.g., carboxymethylchitin, etc.)

Fig. 4. Schematic structure of a chitosan gel microsphere coated with anionic polysaccharide and lipid.

through a polyion complex formation reaction. In the case of lipid-coated microspheres, the microspheres along with dipalmitoyl phosphalidyl choline (DPPC) were dispersed in chloroform. After evaporation of the solvent, microspheres were obtained coated with a DPPC lipid multilayer, which exhibited a transition temperature of a liquid crystal phase at 41.48C. The diameter range of the microspheres was 250–300 nm with a narrow distribution. The stability of the dispersion was improved by coating (Fig. 5) the microsphere with anionic polysaccharide or a lipid multilayer. A comparative study on the release of 5-FU and its derivatives from a polysaccharide-coated microsphere MS (CM) was carried out in physiological saline at 378C. The data indicated that the 5-FU release rate decreased in the order: free 5-FU.carboxymethyl type 5-FU. ester type 5-FU. The results revealed that the coating layers on the microspheres were effective barriers to 5-FU release. Lipid mutilayers with a homogeneous composition generally show a gel–liquid crystal transition. When the temperature is raised to 428C, which is higher than the phase transition of 41.48C, the amount of 5-FU released increased, and the amount of drug delivered decreased at 378C, which is lower than the transition temperature. Due to the improved recognition function of polysaccharide chains for animal cell membranes, delivery systems from polysaccharide-coated microspheres, MS (CM), seem promising.

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Moreover, the release rate can be controlled via the composition of the HPN and the degree of deacetylation of chitosan.

6.9.3.3. Chitosan microspheres for controlled release of diclofenac sodium Gohel et al. [169] reported on chitosan microspheres containing diclofenac sodium, which were prepared by a coacervation phase separation method. Chitosan and glutaraldehyde were used as coating material and crosslinking agent, respectively. In vivo studies were performed on New Zealand white rabbits. Moreover, the microspheres were found to be stable at 458C for 30 days. Student’s ‘t’ test was performed for the results of in vitro dissolution data for fresh and aged samples (30 days at 458C) and no significant difference was found upon storage.
Fig. 5. Preparation of MS (CM), MS (CML) and MS (CM) polysaccharide. A schematic diagram.

6.9.3.2. Chitosan /gelatin network polymer microspheres In their studies on the pharmaceutical applications of chitin and chitosan, Yao and coworkers [168] reported chitosan / gelatin network polymer microspheres for controlled release of cimetidine. The drug-loaded microspheres were prepared by dissolving chitosan, gelatin (1:1 by weight) and cimetidine in 5% acetic acid. A certain amount of Tween-80 and liquid paraffin at a water-to-oil ratio of 1:10 was added to the chitosan / gelatin mixture under agitation at 650 rpm at 308C. A suitable amount of 25% aqueous glutaraldehyde was added to the inverse emulsion and the system maintained for 2 h. Finally, the liquid paraffin was vaporized under vacuum to obtain microspheres. The drug release studies were performed in hydrochloric acid solution (pH 1.0) and potassium dihydrogen phosphate (pH 7.8) buffer at an ionic strength of 0.1 m / l. A pH-dependent pulsed-release behavior of the hybrid polymer network (HPN) matrix was observed [168].

6.9.3.4. Chitosan–polyethylene oxide nanoparticles as protein carriers Hydrophilic nanoparticulate carriers have many potential applications for the administration of therapeutic molecules. The recently developed hydrophobic–hydrophilic carriers require the use of organic solvents for their preparation and have a limited protein-loading capacity [170–173]. To address these limitations, Calvo et al. [174] reported a new approach for the preparation of nanoparticles made solely of hydrophilic polymer. The preparation technique, based on an ionic gelation process, is extremely mild and involves a mixture of two aqueous phases at room temperature (Fig. 6). One phase contains the chitosan (CS) and a diblock copolymer of ethylene oxide and sodium tripolyphosphate (TPP). The size (200–1000 nm) and zeta potential (between 120 and 160 mV) of the nanoparticles can be modulated conventionally by varying the CS / PEO-PPO ratio. Furthermore, using bovine serum albumin (BSA) as a model protein, it was shown that these new nanoparticles have great protein loading capacity (entrapment efficiency up to 80% of the

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Fig. 6. The preparation of CS nanoparticles. A schematic diagram.

390 000 chitosan at pH 4 (less than 7% loss with regard to the 150 g / l initial concentration). Similarly, the encapsulation of various molecules [haemoglobin (Hb), bovine serum albumin (BSA) and dextrans with various molecular weights] in calcium alginate beads coated with chitosan has been reported [176,177]. Their release has been compared and the influence of the dimensions, the chemical composition and the molecular weight of the encapsulated materials have been analysed [176]. The ionic interactions between alginate and chitosan at different pH are depicted in Fig. 7.

protein) and can provide continuous release of the entrapped protein for up to 1 week.

6.9.3.5. Chitosan /calcium alginate beads The encapsulation process of chitosan and calcium alginate as applied to encapsulation of haemoglobin was reported by Huguet et al. [175]. In the first process, a mixture of haemoglobin and sodium alginate is added dropwise to a solution of chitosan and the interior of the capsules thus formed in the presence of CaCl 2 is hardened. In the second method, the droplets were directly pulled off in a chitosan–CaCl 2 mixture. Both procedures lead to beads containing a high concentration of haemoglobin (more than 90% of the initial concentration (150 g / l) is retained inside the beads) provided the chitosan concentration is sufficient. The molecular mass of chitosan (245 000 or 390 000 Da) and the pH (2, 4, or 5.4) had only a slight effect on the entrapment of haemoglobin, the best retention being obtained with beads prepared at pH 5.4. The release of haemoglobin during bead storage in water was found to be dependent on the molecular weight of chitosan. The best retention during storage in water was obtained with beads prepared with a high molecular weight chitosan solution at pH 2.0. Considering the total loss in haemoglobin during bead formation and after 1 month of storage in water, the best results were obtained by preparing the beads in an 8 g / l solution of

6.9.3.6. Multiporous beads of chitosan Several researchers [178,179] have studied simple coacervation of chitosan in the production of chitosan beads. In general, chitosan is dissolved in aqueous acetic acid or formic acid. Using a compressed air nozzle, this solution is blown into NaOH, NaOH–methanol, or ethylenediamine solution to form coacervate drops. The drops are then filtered and washed with hot and cold water successively. Varying the exclusion rate of the chitosan solution or the nozzle diameter can control the diameter of the droplets. The porosity and strength of the beads correspond to the concentration of the chitosan– acid solution, the degree of N-deacetylation of chitosan, and the type and concentration of coacervation agents used. The chitosan beads described above have been applied in various fields, viz. enzymatic immobilization, chromatographic support, adsorbent of metal ions, or lipoprotein, and cell cultures. It was confirmed that the porous surfaces of the chitosan beads form a good cell culture carrier. Hayashi and Ikada [180] immobilized protease onto porous chitosan beads with a spacer and found that the immobilized protease had higher pH, and thermal storage stability, and exhibited higher activity towards the small ester substrate N-benzyl-L-arginine ethyl ester. In addition, Nishimura et al. [178] investigated the possibilities of using chitosan beads as a carrier for the cancer chemothera-

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higher release rates at pH 1–2 than at pH 7.2–7.4. The effect of the amount of drug loaded, the molecular weight of chitosan and the crosslinking agent on the drug-delivery profiles have been reported [181–183].

Fig. 7. Schematic representation of the ionic interactions between alginate and chitosan: (a) pH 5.4; (b) pH 2.0.

peutic adriamycin. Recently, Sharma et al. [181–183] prepared chitosan microbeads for oral sustained delivery of nefedipine, ampicillin and various steroids by adding these drugs to chitosan and then entering a simple coacervation process. These coacervate beads can be hardened by crosslinking with glutaraldehyde or epoxychloropropane to produce microcapsules containing rotundine [167]. The release profiles of the drugs from all these chitosan delivery systems were monitored and showed, in general,

6.9.4. Chitosan-based transdermal drug delivery systems Thacharodi and Rao [184–186] reported permeation-controlled transdermal drug delivery systems (TDS) using chitosan. Studies on propranolol hydrochloride (prop-HCl) delivery systems using various chitosan membranes with different crosslink densities as drug release controlling membranes and chitosan gel as the drug reservoir have been performed. The physicochemical properties of the membranes have been characterized and the permeability characteristics of these membranes to both lipophilic and hydrophilic drugs have been reported [184,185]. In vitro evaluations of the TDS devices while supported on rabbit pinna skin were carried out in modified Franz diffusion cells [186]. The in vitro drug release profiles showed that all devices released propHCl in a reliable, reproducible manner. The drug release was significantly reduced when crosslinked chitosan membranes were used to regulate drug release in the devices. Moreover, the drug release rate was found to depend on the crosslink density within the membranes. It was observed that the device constructed with a chitosan membrane with a high crosslink density released the minimum amount of drug. This is due to the decreased permeability coefficient of crosslinked membranes resulting from the crosslink points. 6.10. Biotechnology 6.10.1. Preparation of biotechnological materials Chitin has two hydroxyl groups, while chitosan has one amino group and two hydroxyl groups in the repeating hexosamide residue. Chemical modification of these groups and the

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

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regeneration reaction gives rise to various novel biofunctional macromolecular products having the original organization or new types of organization.

6.10.2. Cell-stimulating materials 6.10.2.1. In plants Mainly two kinds of extracellular chitinase were found in the normal cell suspension culture of rice (Oryza sativa L. var. japonica cv. Koshihikari). In the presence of a chitin oligosaccharide mixture (degree of polymerization 2–8), however, the extracellular chitinase activity increased about three-fold over the control on secreting an additional extracellular new chitinase isoform. These three chitinase isoforms are one group of pathogenesis-related (PR) proteins in plants [187]. Soyabeans were coated with a thin layer of depolymerized chitin, carboxymethyl (CM)chitin and hydroxyethyl (HE)-chitin, and the seeds were cultured in the field. It was observed that the seed chitinase increased 1.5–2.0-fold, the seed germination rate increased by 6%, the pod number increased by 9%, the plant dry weight increased by 8%, and the crop yield also increased by 10–12% over the control [188]. Dressing with chitin films, sponges and fibres enhanced chitinase activity in tree-bark tissues around wounds up to four-fold over the control. The chitin films, which were implanted in or used to dress the tree-bark tissues, were digested within 4 to 24 weeks thereafter and were assimilated into the wounded bark tissues. The fate of N-acetyl-D-glucosamine in plant tissue is unknown. Phenylalanine ammonia-lyase was stimulated by treatment with chitin, and lignin formation in the plant increased. As a result, wound healing was accelerated [187]. 6.10.2.2. In animals Extracellular lysozyme activity was enhanced in in vitro cultures of several mammalian cells by treatment with chitin and its derivatives. As a result, connective tissue formation was stimu-

lated, and the self-defence function against microbial infection was enhanced at the cellular level. On the basis of these results, several chitin and chitosan dressing materials (discussed in the foregoing sections) have been developed commercially for the healing treatment of human and animal wounds.

6.10.3. Antibacterial agents The growth of Escherichia coli was inhibited in the presence of more than 0.025% chitosan. Chitosan also inhibited the growth of Fusarium, Alternaria and Helminthosporium. The cationic amino groups of chitosan probably bind to anionic groups of these microorganisms, resulting in growth inhibition [189]. 6.10.4. Blood anti-coagulants ( heparinoids) Chitin and chitosan sulphates have blood anticoagulant and lipoprotein lipase (LPL)-releasing activities. Chitin 3,6-sulfate showed about two-fold anticoagulant activity and 0.1fold LPL-releasing activity over those of heparin; the sulfate derivatives might be usable as heparinoids for artificial blood dialysis [187]. 6.10.5. Anti-throbogenic and haemostatic materials Chitosan fibres were found to be thrombogenic and haemostatic in an in vitro test, and N-hexanoyl and N-octanoyl chitosan fibres were anti-thrombogenic. Chitosan fibres can be used as haemostatic material; N-hexanoyl and Noctanoylchitosan fibres are used as anti-thrombogenic materials [190]. 6.11. Chitosan as fat trapper
One of the characters in a recent movie, ‘The Full Monty’, had a memorable line: ‘‘The less I eat, the fatter I get.’’ Its a phenomenon that plagues many dieters who eat less and lose muscle instead of fat. As a result, their metabolism slows down and it becomes more and more difficult to control weight. Fortunately, it is not too difficult to lose the right stuff, fat, while

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

improving muscle tone, metabolism and health. Many supplements can help in the fat reduction process, including pyruvate and chitosan. Pyruvate, found in red apples, some types of cheese, and red wine, stimulates fat loss and boosts exercise performance. Chitosan attaches itself to fat in the stomach before it is digested, thus trapping the fat and preventing its absorption by the digestive tract. Fat in turn binds to the chitosan fibre, forming a mass which the body cannot absorb, and which is eliminated by the body. Chitosan fibre differs from other fibres in that it possesses a positive ionic charge, which gives it the ability to bond chemically with the negatively charged lipids, fats and bile acids [191–193]. 7. Conclusion Chitin and chitosan have a wide range of applications. They may be employed, for example, to solve numerous problems in environmental and biomedical engineering. Chitin derivatives including partially deacetylated chitosan can be easily molded to various forms and their derivatives are digested in vivo by lysozomal enzymes. Thus, it appears that this material can be a most interesting candidate for use as a carrier of a variety of drugs for controlledrelease applications. Lately, the transdermal absorption promoting characteristics of chitosan have been exploited, especially for nasal and oral delivery of polar drugs to include peptides and proteins and for vaccine delivery. These properties, together with the very safe toxicity profile, make chitosan an exciting and promising excipient for the pharmaceutical industry for present and future applications. Thanks to the bioactivities of chitosan itself, its formulations with drugs may have dual therapeutic effects. Acknowledgements The author thanks Dr K.G. Ramachandran Nair, Central Institute of Fisheries Technology,

Kochi, India, for providing the sample of chitosan. The author is grateful to the Council of Scientific and Industrial Research (CSIR), Ministry of Human Resource Development Groups, Govt. of India, New Delhi, for financial assistance to carry out this research. The author is indebted to the referees for a thorough revision of the manuscript.

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