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Review
A review of chitin and chitosan applications
qMajeti 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 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 the ceans, insects, etc., is well known to consist of major source of surface pollution in coastal 2-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 nomenclature low, in spite of the presence of nitrogen. It is a with respect to the degree of N-deacetylation highly insoluble material resembling cellulose has not been defined between chitin and in its solubility and low chemical reactivity. It chitosan [1,2]. The structures of cellulose, chitin may be regarded as cellulose with hydroxyl at and chitosan are shown in Fig. 1. Chitin and chitosan are of commercial interest due to their high 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 with
his 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 and
73560.
biodegradability are much more limited than
E-mail address: mnvrkumar@mailcity.com (M.N.V. Ravi
Kumar). those of natural polymers such as cellulose,
1381-5148 / 00 / $ – see front matter 2000 Elsevier Science B.V. All rights reserved.
P I I : S 1 3 8 1 - 5 1 4 8 ( 0 0 ) 0 0 0 3 8 - 9
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]. Chemi- cally modified chitin and chitosan structures resulting in improved solubility in general or- ganic 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 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, similar these naturally abundant materials also exhibit a to those for the production of citric acid from limitation 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.
tion, some soluble glycans are removed [24]. 4. Properties of chitin and chitosan The 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, alginic lution of calcium carbonate which is present in
acid, agar, agarose and carragenans, are neutral crab shells in high concentrations. The resulting
chitin is deacetylated in 40% sodium hydroxide or acidic in nature, whereas chitin and chitosan at 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 metal ions and optical structural characteristics [29].
3. Economic aspects Like cellulose, chitin functions naturally as a structural polysaccharide, but differs from cellu- The production of chitin and chitosan is
lose in its properties. Chitin is highly hydro- currently based on crab and shrimp shells
phobic and is insoluble in water and most discarded by the canning industries in Oregon,
organic solvents. It is soluble in hexafluoro- Washington, Virginia and Japan and by various
isopropanol, hexafluoroacetone, chloroalcohols finishing fleets in the Antarctic. Several coun-
in conjugation with aqueous solutions of miner- tries possess large unexploited crustacean re-
al acids [24] and dimethylacetamide containing sources, e.g. Norway, Mexico and Chile [25].
5% lithium chloride. Chitosan, the deacetylated The production of chitosan from crustacean
product of chitin, is soluble in dilute acids such shells obtained as a food industry waste is
as acetic acid, formic acid, etc. Recently, the gel economically feasible, especially if it includes
forming ability of chitosan in N-methylmor- the recovery of carotenoids. The shells contain
pholine N-oxide and its application in controlled considerable quantities of astaxanthin, a carot-
drug release formulations has been reported enoid that has so far not been synthesized, and
[30–32]. The hydrolysis of chitin with concen- which is marketed as a fish food additive in
trated acids under drastic conditions produces aquaculture, especially for salmon.
relatively pure D-glucosamine.
To produce 1 kg of 70% deacetylated
The nitrogen content of chitin varies from 5 chitosan from shrimp shells, 6.3 kg of HCl and
to 8% depending on the extent of deacetylation, 1.8 kg of NaOH are required in addition to
whereas the nitrogen in chitosan is mostly in the nitrogen, process water (0.5 t) and cooling
form of primary aliphatic amino groups.
water (0.9 t). Important items for estimating the
Chitosan, therefore, undergoes reactions typical production cost include transportation, which
of amines, of which N-acylation and Schiff varies 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 substituted prawn waste contained 23% and dry squilla glucans.
contained 15% chitin [26]. They have also N-Acylation with acid anhydrides or acyl reported that the chitinous solid waste fraction halides introduces amido groups at the chitosan of the average Indian landing of shell fish nitrogen. Acetic anhydride affords fully ranges from 60 000 to 80 000 tonnes [27,28]. acetylated chitins. Linear aliphatic N-acyl Chitin and chitosan are now produced commer- groups above propionyl permit rapid acetylation cially in India, Japan, Poland, Norway and of hydroxyl groups. Higher benzoylated chitin is Australia. 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 becomes dimines and ketimines with aldehydes and soluble in dilute aqueous acetic and formic ketones, respectively. Reaction with ketoacids acids. In chitin, the acetylated units prevail followed by reaction with sodium borohydride (degree of acetylation typically 0.90). Chitosan produces glucans carrying proteic and non- is the fully or partially N-deacetylated derivative proteic amino groups. N-Carboxymethyl of chitin with a typical degree of acetylation of chitosan is obtained from glyoxylic acid. Exam- less than 0.35. To define this ratio, attempts ples of non-proteic amine acid glucans derived have been made with many analytical tools from chitosan are the N-carboxybenzyl [35–44], which include IR spectroscopy, chitosans obtained from o- and p-phthalal- pyrolysis gas chromatography, gel permeation dehydic acids [24,25]. Chitosan and simple chromatography and UV spectrophotometry, aldehydes produce N-alkyl chitosan upon hydro- first derivative of UV spectrophotometry, H-1
genation. The presence of the more or less NMR spectroscopy,13C solid state NMR, ther- bulky substituent weakens the hydrogen bonds mal analysis, various titration schemes, acid of chitosan; therefore N-alkyl chitosans swell in hydrolysis and HPLC, separation spectrometry water 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 weight
Chitosan molecular weight distributions have 4.1. 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 scattering homopolymer, while chitin and chitosan are [47]. Viscometry is a simple and rapid method heteropolymers. Neither random nor block for the determination of molecular weight; the orientation is meant to be implied for chitin and constants a and K in the Mark–Houwink chitosan. The properties of chitin and chitosan equation have been determined in 0.1 M acetic such as the origin of the material (discussed in acid and 0.2 M sodium chloride solution. The the previous section), the degree of N-deacetyla- intrinsic viscosity is expressed as
tion, molecular weight and solvent and solution
a 23 0.93
properties are discussed in brief. Glycol chitin, a [h] 5 KM 5 1.81 3 10 M partially O-hydroxyethylated chitin, was the
first derivative of practical importance; other
The charged nature of chitosan in acid solvents derivatives and their proposed uses are shown in
and chitosan’s propensity to form aggregation Table 1.
complexes require care when applying these constants. Furthermore, converting chitin into chitosan lowers the molecular weight, changes 4.1.1. Degree of N-acetylation
the degree of deacetylation, and thereby alters An important parameter to examine closely is
the charge distribution, which in turn influences the degree of N-acetylation in chitin, i.e. the
the agglomeration. The weight-average molecu- ratio of 2-acetamido-2-deoxy-D-glucopyranose
6 6
lar weight of chitin is 1.03310 to 2.5310 , to 2-amino-2-deoxy-D-glucopyranose structural
but the N-deacetylation reaction reduces this to units. This ratio has a striking effect on chitin
5 5
solubility and solution properties. Chitosan is 1310 to 5310 [48].
Table 1
Chitin derivatives and their proposed uses
Derivative Examples Potential uses
N-Acyl chitosans Formyl, acetyl, propionyl, butyryl, hexanoyl, Textiles, membranes octanoyl, decanoyl, dodecanoyl, tetradecanoyl, and medical aids lauroyl, 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 collection acid 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, and insecticides Semisynthetic resins Copolymer of chitosan with methyl methacrylate, Textiles of chitosan polyurea-urethane, poly(amideester), acrylamide-
maleic anhydride
Natural polysacchar- Chitosan glucans from various organisms Flocculation and
ide complexes, metal ion chelation
miscellaneous Alkyl chitin, benzyl chitin Intermediate, serine
protease purification Hydroxy butyl chitin, cyanoethyl chitosan Desalting filtration,
dialysis and insulating papers
Hydroxy ethyl glycol chitosan Enzymology, dialysis
and special papers
Glutaraldehyde chitosan Enzyme
immobilization
Linoelic acid–chitosan complex Food additive and
anticholesterolemic 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 formed Both 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 of number 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 2 degrade before melting, which is typical for report, many solvent systems including organic polysaccharides with extensive hydrogen bond- solvents and mixtures of inorganic salts and ing. 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 14 polymer 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 3 viscosity must be known. Comparative data h at 1808C and 10 atm pressure. It was pointed from solvent to solvent are not available. As a out that 6 to 10% of solids of N-deacetylated general rule, the maximum amount of polymer chitin can be brought into acidic solution at is dissolved in a given solvent towards a room temperature. Aqueous acetic acid was homogeneous 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 a cussed in the following sections). A coagulant is filter press to remove impurities, fibres were required for polymer regeneration or solidifica- spun. Chemicals incompatible with chitin were tion. The nature of the coagulant is also highly suggested as coagulants. The resultant fibres dependent on the solvent and solution properties were washed and dried under tension. The final as well as the polymer used [54,75]. product fibres had a round- to heart-shaped cross section with a tensile breaking load of 35 kg / mm (345 Pa). The fibres possessed a dull2
5. Chitin and its derivatives in fibre luster similar to natural silk, leading to the
formation suggestion that the N-deacetylated chitin fibres
would make good artificial hair. The collection 5.1. Natural microfibriller arrangement
and recycling of chitin from small-scale con- sumers was also suggested. Clark and Smith Chitin has been known to form microfibrillar
reported a procedure for producing fibres by arrangements in living organisms. These fibrils
dissolution of chitin at 958C in presaturated are usually embedded in a protein matrix and
solutions 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 analysis ters as large as 25 nm. The presence of mi-
showed a high degree of orientation. Solvent crofibrils suggests that chitin has characteristics
removal was not successful even at 2008C.
which make it a good candidate for fibre
Lithium iodide was implied to have behaved in spinning. To spin chitin or chitosan fibres, the
the same manner. A ratio of 5 mol lithium raw polymer must be suitably redissolved after
thiocyanate per mole anhydroglucose unit was removal of extraneous material such as calcium
found to exist. This is comparable to the carbonate and proteins, which encase the mi-
cellulose–lithium thiocyanate compound. Cellu- crofibrils.
lose solubility and the role of solvate / salt complexes have been reviewed in detail [52,53].
5.2. Fibre formation — in retrospection
Recently, Rathke and Hudson published a re- Numerous methods of spinning chitin fibres view highlighting the ability of chitin and have 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 room temperature. Fibres were extruded through a 5.3.1. Halogenated solvent spin system spinneret of 0.04 and 0.06 mm diameter into an In 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 filaments chitin. Such a system was chloroethanol and was in the range of 1.67 to 3.1 g / d with an sulfuric acid. The precipitation of chitin in elongation from 8.7 to 20.0%. The strength of fibrillar form in water, methanol, or aqueous the fibres was improved by leaving them in a ammonium 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 suitable were 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 elongations forcement Agency, class IV controlled sub- suggest that the halogenated solvents act as stance), and 20% methylene chloride over a plasticizers.
period of 30–45 min. A filament was extruded Fuji Spinning Company dissolved chitosan in from this solution using a hypodermic needle a mixture of water and dichloroacetic acid and acetone as the coagulant. The filament was (DCA). The 6.44% chitosan acetate salt solution then 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 mm deionized 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 tensile relative 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 of 0.0830.10 mm, yielding a tensile strength of 72 formic acid (FA), DCA and diisopropyl ether as kg / mm (710 Pa) and a breaking elongation of2 a solvent system. Chitin was cycled several 13%. 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 of structure. It had a tensile strength of 104 kg / DCA. Diisopropyl ether was then added to mm2 (1026 Pa) and a breaking elongation of reduce the solution viscosity to below 199 poise 44% [56]. Syringing a filament cannot be and tensile properties were also reported [60]. It interpreted as conclusive evidence for a possible is noteworthy that the wet strength drops to wet spinning process. While syringe extrusion below 0.50 g / d but that the elongation increases might indicate the selection of a coagulant, it to 13%.
would be rather surprising to obtain meaningful A TCA / dichloromethane spin system is also tensile data. Shear forces in a spinneret are described by the Unitika Co. Three parts chitin much greater than those experienced in a sy- were dissolved in 50 parts TCA and 50 parts
ringe 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 with such as chloromethane, dichloromethane, and water, and dried. The fibres had a tensile 1,1,2-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 are TCA / 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 can methanolic 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 system
patent using a 60:40 TCA / trichloroethylene In 1978, Rutherford and Austin summarized spin dope mixture. Tensile properties were the problems encountered in finding a solvent unavailable [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 kg / cm pressure into acetone to form filaments.2 obtained within 2 h with these systems. A The extrusion die had holes of 0.07 mm diam- filament was extruded from the solution using a eter, indicating a jet velocity of 8.8 m / min and 15-gauge needle into an acetone coagulation a take-up of 5 m / min. The coagulation bath was bath. This was followed by more washing and maintained at 188C. The filaments were washed drawing in acetone. The final filament was with acetone at 188C for 10 min, rewound at 4.5 washed in deionized water. Tensile properties m / 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. The with a tenacity of 2.65 g / d [63]. A similar resultant dry tensile strengths for different crab system using four parts chitin in the same and shrimp species ranged from 24 to 60 kg / solvent but a 40-hole die of 0.08 mm diameter mm (236–592 Pa) [66].2
each was also used. The jet velocity was 10.4 Russian researchers spun chitin fibres out of m / min into a 258C acetone bath. A rewinding at DMAc / NMP solutions containing 5% chitin 7 m / min followed the first take-up roll at 5 and 5% LiCl (based on chitin content). These m / min. The total denier was 175; however, no fibres were drawn in a 50:50 ethanol / ethylene tensile properties were reported [64]. glycol bath, giving an average yield strength of Some of the halogenated solvent systems 390 MPa with 3% elongation. An initial attained dry tenacities of above 3 g / d; however, modulus of 2 GPa was also reported. Scanning the low wet tenacities were still undesirable. electron microscopy showed fibres with a round Although the fibre characterization was much fibrillar cross section [67]. A follow-up study better for these systems, the polymer characteri- showed a decrease in the elasticity modulus and zation lacked molecular weight as well as relative elongation with increase in the degree degree 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 amorphous chitin degradation in these solvents. Although regions was observed with increase in degree of anhydrous coagulation baths were used and acetylation [68].
compared, fibres were neutralized in aqueous The amide–lithium systems showed some of media. A study in completely anhydrous sys- the best dry tenacities, although they still lack tems would be of interest, since it may lead to adequate wet tenacities. The low wet tenacities more densely consolidated fibres. The im- are probably due to low crystallinity and poor plementation of these spin systems represents a consolidation of the fibre. The fibres and spin problem due to the nature of the solvents. TCA dopes were well characterized but the polymers and 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. Photography comparison could not be made. A problem with
Chitosan has important applications in photo- this spin system is the removal and recovery of
graphy due to its resistance to abrasion, its lithium from the fibre. The lithium acts as a
optical characteristics, and film forming ability.
Lewis acid by solvating the chitin amide group.
Silver complexes are not appreciably retained It is unclear if this can be completely reversed
by chitosan and therefore can easily be pene- through washing, once the fibres are formed.
trated 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 pro-
6.2. Cosmetics cess for chitosan fibres by direct dissolution
using a novel solvent system, N-methylmor- For cosmetic applications, organic acids are pholine oxide / water (NMMO / H O), but no2 usually good solvents, chitin and chitosan have interesting tensile data were obtained from these fungicidal and fungistatic properties. Chitosan is preliminary investigations [69]. the only natural cationic gum that becomes viscous on being neutralized with acid. These materials are used in creams, lotions and perma- 6. Applications nent waving lotions and several derivatives have
also been reported as nail lacquers [78].
The interest in chitin originates from the
study of the behaviour and chemical characteris- 6.3. Chitosan as an artificial skin tics of lysozyme, an enzyme present in human
body 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 ill have 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 must may 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 crippling differentiation 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 on limiting factor in its utilization. Despite this healing and fibroplasia of wounds made by limitation, various applications of chitin and scalpel insertions in skin and subcutaneous modified 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 artificial of 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 synthesis urine and pancreatic juice, which are problem of neodermal tissue [80]. It appears that areas 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 considered chitin 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 chelation
has received much attention [70,77]. Their use 6.3.1. Chitin- and chitosan-based dressings in the apparal industry, with a much larger Chitin and chitosan have many distinctive scope, 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 degraded chitosan by tissue enzymes and this material stages of research [84].
was found to be effective in regenerating the Sparkes 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 the
butyl chitosan dressing for treating plastic chitosan in water in the presence of a suitable
surgery donor sites. A solution of N-carboxy- acid, maintaining the pH of the solution at about
butyl chitosan was dialyzed and freeze-dried to 2–3, followed by adding the gelatin dissolved in
produce a 1032030.5 cm3 soft and flexible water. The ratio of chitosan and gelatin is 3:1 to
pad, which was sterilized and applied to the 1:3. To reduce the stiffness of the resulting
wound. This dressing could promote ordered dressing a certain amount of plasticizers such as
tissue regeneration compared to control donor glycerol and sorbitol could be added to the
sites. Better histoarchitectural order, better vas- mixture. Dressing film was cast from this
cularization and the absence of inflammatory solution on a flat plate and dried at room
cells were observed at the dermal level, while temperature. It was claimed that, in contrast to
fewer aspects of proliferation of the malpighian conventional biological dressings, this ex-
layer were reported at the epidermal level.
perimental dressing displayed excellent adhe-
The British Textile Technology Group sion to subcutaneous fat.
(BTTG) patented a procedure for making a Nara et al. [86] patented a wound dressing
chitin-based fibrous dressings [90–93]. In this comprising a nonwoven fabric composed of
method the chitin / chitosan fibres were not made chitin fibres made by the wet spinning tech-
by the traditional fibre-spinning technique and nique. In one of the examples, chitin powder
the raw materials were not from shrimp shell was ground to 100 mesh and treated in 1 M HCl
but from micro-fungi instead. The procedure for 1 h at 48C. It was then heated to 908C where
can 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 a powder, and rinsed repeatedly followed by culture of Mucor mucedo growing in a drying. The resultant chitin was dissolved in a nutrient solution.
dimethylacetamide solution containing 7 wt% (ii) Culture washing and treatment with lithium chloride to form a 7% dope. After NaOH to remove protein and precipitate filtering 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 fibres rate 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 mechanical to obtain a filament of 0.74 dtex with a strength strength.
of 2.8 g / den. The filaments were then cut into
staple 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 different dressing, Beschitin W, composed of chitin non- from normal spun fibres. They have highly woven fabric which proved to be beneficial in branched and irregular structures. The fibres are clinical practice. Kim and Min [88] have de- unmanageably brittle when they are allowed to veloped a wound-covering material from poly- dry and a plasticizer has to be associated with electrolyte complexes of chitosan with sulfon- the whole process and a wet-laid matt is used as ated 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-methylpyrrolidinone
hence some infants fed cow’s milk may have chitosan, which is believed to be very promising
indigestion. Many animals and some humans in medical applications. This polymer is claimed
(including the elderly) have similar lactose to 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. The
the utilization of whey may be improved if the advantages include healing of wounded mensi-
diet contains small amounts of chitinous materi- cal tissues, and of decubitus ulcers, depression
al. This improvement is attributed to the change of capsule formation around prostheses, limita-
in the intestinal microflora brought about by the tion of scar formation and retraction during
chitinous supplement [98]. Chickens fed a com- healing. Some wound-dressing samples were
mercial broiler diet containing 20% dried whey prepared from an aqueous solution of this 5-
and 2 or 0.5% chitin had significantly improved methylpyrrolidone chitosan, which was dialyzed
weight again compared to controls [99,100].
and laminated between stainless steel plates and
The feed efficiency ratio shifted from 2.5 to freeze-dried to yield fleeces. The material could
2.38 due to incorporation of chitin in the feed be fabricated into many different forms, such as
[100].
filaments, nonwoven fabrics, etc. Once applied to a wound, 5-methylpyrrolidinone chitosan
6.5. Opthalmology becomes 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 optical butyric 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 immunological polymers with molecular weights high enough
compatibility. Contact lenses are made from to form fibres were obtained and dibutyryl
partially depolymerized and purified squid pen chitin fibres were made by dry spinning a 20–
chitosan by spin casting technology and these 22% solution into acetone. The fibres have
contact lenses are clear, tough and possess other tensile 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, water fibres with good tensile properties could be
content and oxygen permeability. The anti- obtained by alkaline hydrolysis of dibutyryl
microbial and wound healing properties of chitin fibres without destroying the fibre struc-
chitosan along with an excellent film capability ture.
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 engineering in 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 environmental The N-acetylglucosamine (NAG) moiety problems.
present in human milk promotes the growth of
bifido bacteria, which block other types of 6.6.1. Metal capture from wastewater
microorganism 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 many were 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 sorption of Hg21 by chitosan depends upon the rate of diffusion of dyes in chitosan is similar to period of treatment, the particle size, initial that in cellulose. Only for basic dyes has
21 chitosan a low affinity. Chitosan is versatile in concentration of Hg and quantity of chitosan.
sorbing metals and surfactants, as well as to Jha et al. [104] studied the adsorption of
21 derivatization to attract basic dyes and other
Cd on chitosan powder over the concentration
moieties (e.g., proteins from food processing range of 1–10 ppm using various particle sizes
plants).
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 an Hydroxymethyl chitin and other water-solu-
increase in the dye sorption rate, but diminishes ble derivatives are useful flocculents for anionic
total sorption capacity [111]. However, these waste streams. Chitosan N-benzylsulfonate de-
effects are small and normal wastewater tem- rivatives were used as sorbents for removal of
perature variations do not significantly affect the metal ions in an acidic medium by Weltrowski
overall decolorization performance [112]. Also, et al. [105]. The selective adsorption capacity
the wastewater pH may be an important factor for metal ions of amidoximated chitosan bead-
in the sorption of certain dyes onto chitosan g-PAN copolymer has been studied by Kang et
because, at low pH, chitosan’s free amino al. [106]. These investigations clearly indicate
groups are protonated, causing them to attract that chitosan has a natural selectivity for heavy
anionic dyes. Contact time or, inversely, flux metal ions and is useful for the treatment of
(wastewater flow per unit cross-sectional area) wastewater.
affects sorption in a complex manner in a fixed McKay 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 within
bed penetration and boundary layer effects. At the temperature range 25–608C at near neutral
high flux, the diversion of liquid into larger pH. Further adsorption parameters for the re-
channels around particles and turbulent flow moval of these metal ions were reported by
occur. In general, a low flux tends to give more Yang et al. [108]. Maruca et al. [109] used
complete contaminant removal.
chitosan flakes of 0.4–4 mm for the removal of
For almost all the treatment strategies, a Cr(III) from wastewater. The adsorption capaci-
major factor which has not yet been adequately ty increased with a decrease in the size of the
characterized is the effect of typical wastewater flakes, which implied that metal ions were
contaminants on decolorization efficiencies. In preferably adsorbed on the outer surface of
typical dyeing systems it is well known that chitosan in the removal of Cr(III) from the
certain additives such as salt and surfactants can wastewater. 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 design of any decolorization system.
6.6.2. Colour removal from textile mill
Finally, a factor which significantly increases effluents
the 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 chitin
possible. 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 6.7. Paper finishing
Knorr examined the dye-binding properties
by weighing 0.5 or 2.0 g chitin or chitosan in Chitosan has been reported to impart wet centrifuge tubes, adding 20 g of aqueous dye strength to paper [117]. Hydroxymethyl chitin solution (5 to 49 mg dye / l) and then shaking and other water-soluble derivatives are useful the 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 significant supernatant decanted and the water uptake of product. The entrepreneur in paper making can chitin 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 as
a blank. The weight of the supernatant was used 6.8. Solid-state batteries as the basis for the calculation of the total
amount of dye bound or released. pH adjust- Chitosan is insoluble in water. This poses a ment 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 be HCl to a slurry of 0.5 g chitin / chitosan and 10 any water present in the chitosan which can act ml 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 obtained values below 5.5 and no dye-binding measure- from chitosan alone. Chitosan is a biopolymer ments could be obtained. which can provide ionic conductivity when The effects of dye concentration and chitin / dissolved in acetic acid. The conductivity is due chitosan dye solution ratios on dye-binding to the presence of protons from the acetic acid capacity and water uptake of chitin and chitosan solution. The transport of these protons is are discussed in detail elsewhere [114]. Marked thought to occur through many microvoids in differences between water uptake of chitin and the polymer since the dielectric constants from chitosan exist with chitosan taking more water piezoelectric studies are small. The choice of a than chitin. The difference may be due to more suitable electrode material may produce a differences in crystallinity of the products or better battery system [118].
due to differences in the amount of salt-forming
groups [115]. Differences in the amount of 6.9. Drug-delivery systems covalently bound protein residue might also
affect 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 and with the dye-binding capacity of chitin and reproducible release of an agent into a specific chitosan [116]. The effect of pH on the dye- environment over an extended period of time binding capacity of chitin and chitosan was also has much significant merit. It creates a desired studied. A decline in the dye-binding capacity environment with optimal response, minimum above 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, chitosan matrix formulations appear to float and gradual- cy and reliability of drug therapy. They regulate
ly swell in an acid medium. All these interesting the drug release rate and reduce the frequency
properties of chitosan make this natural polymer of drug administration to encourage patients to
an ideal candidate for controlled drug release comply with dosing instructions. Conventional
formulations. Many excellent reviews and books dosage forms often lead to wide swings in
deal with the properties, chemistry, biochemis- serum drug concentrations. Most of the drug
try and applications of chitin, chitosan and their content 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 whose
6.9.1. Hydrogels based on chitin and chitosan actions correlate with their serum drug con-
Hydrogels are highly swollen, hydrophilic centration, the sharp fluctuations often cause
polymer networks that can absorb large amounts unacceptable side-effects at the peaks, followed
of water and drastically increase in volume. It is by 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 of
lar structure, the gel structure, and the degree of biodegradability into the system. A number of
crosslinking, but also on the content and state of degradable polymers are potentially useful for
the water in the hydrogel. Hydrogels have been this purpose, including synthetic as well as
widely 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 contract involves their slow and controllable diffusion
in response to external pH [139–141] have been from / 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 to ceutical 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 molecular polymers or dispersed in a polymeric matrix of weight and protein drug delivery [142]. It is such macromolecules may be released by ero- known that the release of drugs from hydrogels sion / degradation of the polymer. Therapeutic depends on their structure or their chemical molecules, complexed by polymers, may also be properties in response to pH [143,144]. These released 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 and able [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 polymers activities which prevent or weaken drug irrita- used are biodegradable to obtain a desirable device to control drug release [146]. Thus, to be able to design hydrogels for a particular applica- tion, it is important to know the nature of the systems in their environmental conditions. Some recent advances in controlled-release formula- tions 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
Fig. 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 also terpenetrating polyether polymer network. The studied the drug release behaviour using silver pH sensitivity, swelling and release kinetics and sulfadiazine as a model drug [152].
structural changes of the gel in different pH
solutions 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 chitin
structure and the degree of crosslinking, but also Lee and Kim [153] reported a procedure for on 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 polymerization study of the physical state of water in the using low toxic stannous octoate as catalyst or hydrogels is of great importance to understand without catalyst (Fig. 3). Investigations of the the nature of interactions between absorbed thermal and mechanical properties were carried water and polymers. Yao et al. [149] studied the out. Vitamin A, vitamin E and riboflavin were dynamic water absorption characteristics, state used as model drugs [154,155]. However, there of 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 and
some 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 biomedical the 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 network strength 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. The applied. 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 acetic sults 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].
6.9.1.2. Semi-IPN hydrogel polymer networks ofb-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 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 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 starch films, followed by subsequent crosslinking with with chitin (potato starch / chitin), and with 2,2-dimethoxy-2-phenylacetophenone as non- chitosan (potato starch / chitosan). The disinte- toxic photo initiator by UV irradiation. They gration properties of tablets made from these studied the crystallinity and thermal and me- powders, in comparison with those of combined chanical 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 and based on crosslinked chitosan / gelatin with a chitosan was greater than that of the powder glutaraldehyde hybrid polymer network. They with crystalline cellulose. The reported hardness observed drastic swelling of the gels at acidic of the tablets follows the order: chitosan pH in comparison to basic solutions. tablets.MCC.chitin. In disintegration studies, Levamisole, cimetidine and chloramphenicol tablets containing less than 70% chitin or were used as model drugs. A pH-dependent chitosan passed the test. Moreover, the ejection release 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 its
swelling 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 complex
Homogenous erosion of the matrix and a near Recently, chitosan has gained importance as a zero-order release of ampicillin trihydrate were disintegration agent due to its strong ability to observed. They reported the thermal properties absorb water. It has been observed that chitosan of the chitosan–amine oxide gel in a further contained in tablets at levels below 70% acts as
study [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. The lulose (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 mechanism their versatility, have been reported to be useful with a rate constant that increased with an diluents 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, becoming
potato starch negligible in the case of theophylline.
Sawayanagi et al. [161] reported the fluidity Recently, Mi et al. [164] have reported and compressibility of combined powders of alginate as an anionic polyelectrolyte to control lactose with chitin (lactose / chitin), with the swelling and erosion rates of chitosan tablets
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 micro- scopy was used to examine the swelling / diffu- sion mechanism of various tablets [164].
6.9.3. Microcapsules /microspheres of chitosan A ‘microcapsule’ is defined as a spherical
Fig. 4. Schematic structure of a chitosan gel microsphere coated
particle 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, the tion, some related terms are used as well. For microspheres along with dipalmitoyl phos- example, ‘microbeads’ and ‘beads’ are used phalidyl choline (DPPC) were dispersed in alternatively. 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 a Recently, 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 at microspheres related to chitosan. Due to the 41.48C. The diameter range of the microspheres attractive 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 by a survey of the applications in controlled drug coating (Fig. 5) the microsphere with anionic release formulations is appropriate. Moreover, polysaccharide or a lipid multilayer.
microcapsule and microsphere forms have an A comparative study on the release of 5-FU edge over other forms in handling and adminis- and its derivatives from a polysaccharide-coated
tration. microsphere MS (CM) was carried out in
physiological saline at 378C. The data indicated 6.9.3.1. Crosslinked chitosan microspheres that the 5-FU release rate decreased in the coated 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 the microspheres 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 crystal fluorouracil (5-FU) or its derivative solution of transition. When the temperature is raised to hydrochloric acid of chitosan in toluene con- 428C, which is higher than the phase transition taining 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 delivered glutaraldehyde solution in toluene. At the same decreased at 378C, which is lower than the time, the amino derivatives of 5-FU were transition temperature. Due to the improved immobilized, obviously resulting in an increase recognition function of polysaccharide chains in the amount of drug within the microspheres. for animal cell membranes, delivery systems The microspheres were coated with anionic from polysaccharide-coated microspheres, MS polysaccharides (e.g., carboxymethylchitin, etc.) (CM), seem promising.
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 micro- spheres containing diclofenac sodium, which were prepared by a coacervation phase sepa- ration method. Chitosan and glutaraldehyde were used as coating material and crosslinking agent, respectively. In vivo studies were per- formed on New Zealand white rabbits. More- over, 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.
6.9.3.4. Chitosan –polyethylene oxide
Fig. 5. Preparation of MS (CM), MS (CML) and MS (CM)
polysaccharide. A schematic diagram. nanoparticles as protein carriers
Hydrophilic nanoparticulate carriers have 6.9.3.2. 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 their workers [168] reported chitosan / gelatin net- preparation and have a limited protein-loading work 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 nanoparticles gelatin (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 gelation liquid paraffin at a water-to-oil ratio of 1:10 was process, is extremely mild and involves a added 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 the of 25% aqueous glutaraldehyde was added to chitosan (CS) and a diblock copolymer of the inverse emulsion and the system maintained ethylene oxide and sodium tripolyphosphate for 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 conventionally hydrochloric 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 a an ionic strength of 0.1 m / l. A pH-dependent model protein, it was shown that these new pulsed-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% loss with 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 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 ma- terials have been analysed [176]. The ionic
Fig. 6. The preparation of CS nanoparticles. A schematic dia-
interactions between alginate and chitosan at
gram.
different pH are depicted in Fig. 7.
protein) and can provide continuous release of 6.9.3.6. Multiporous beads of chitosan
the 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 is haemoglobin 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 hot a solution of chitosan and the interior of the and cold water successively. Varying the exclu- capsules thus formed in the presence of CaCl is2 sion rate of the chitosan solution or the nozzle hardened. In the second method, the droplets diameter can control the diameter of the drop- were directly pulled off in a chitosan–CaCl2 lets. The porosity and strength of the beads 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 of g / 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. enzymatic 390 000 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 cell globin, the best retention being obtained with cultures. It was confirmed that the porous beads prepared at pH 5.4. The release of surfaces of the chitosan beads form a good cell haemoglobin 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 beads of chitosan. The best retention during storage in with a spacer and found that the immobilized water was obtained with beads prepared with a protease had higher pH, and thermal storage high molecular weight chitosan solution at pH stability, and exhibited higher activity towards 2.0. Considering the total loss in haemoglobin the small ester substrate N-benzyl-L-arginine during 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 chitosan by 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 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].
6.9.4. Chitosan-based transdermal drug delivery systems
Thacharodi and Rao [184–186] reported per- meation-controlled transdermal drug delivery systems (TDS) using chitosan. Studies on pro- pranolol hydrochloride (prop-HCl) delivery sys- tems 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 diffu- sion cells [186]. The in vitro drug release profiles showed that all devices released prop- HCl 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
Fig. 7. Schematic representation of the ionic interactions between
chitosan membrane with a high crosslink den-
alginate and chitosan: (a) pH 5.4; (b) pH 2.0.
sity released the minimum amount of drug. This is 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, ampicillin
and various steroids by adding these drugs to 6.10. Biotechnology chitosan and then entering a simple coacerva-
tion process. These coacervate beads can be 6.10.1. Preparation of biotechnological hardened by crosslinking with glutaraldehyde or materials
epoxychloropropane to produce microcapsules Chitin has two hydroxyl groups, while containing rotundine [167]. The release profiles chitosan has one amino group and two hydroxyl of 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
