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Reactive & Functional Polymers 46 (2000) 1–27

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Review

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 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
q
high percentage of nitrogen (6.89%) compared
This paper is dedicated to Professor M.N.V. Prasad, Ph.D.,
FNIE (New Delhi), DSc. (hc Colombo), School of Life Sciences,
to synthetically substituted cellulose (1.25%).
University of Hyderabad, Hyderabad, India, who inspired me with This makes chitin a useful chelating agent [1].
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.
E-mail address: mnvrkumar@mailcity.com (M.N.V. Ravi biodegradability are much more limited than
Kumar). 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
2 M.N.V. Ravi Kumar / Reactive & Functional Polymers 46 (2000) 1 – 27

radability, non-toxicity, adsorption properties,


etc.
Recently, much attention has been paid 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,
Fig. 1. Structures of cellulose, chitin and chitosan. chitin production is associated with food indus-
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.
M.N.V. Ravi Kumar / Reactive & Functional Polymers 46 (2000) 1 – 27 3

tion, some soluble glycans are removed [24]. 4. Properties of chitin and chitosan
The processing of crustacean shells mainly
involves the removal of proteins and the disso- Most of the naturally occurring polysac-
lution of calcium carbonate which is present in charides, e.g. cellulose, dextran, pectin, alginic
crab shells in high concentrations. The resulting acid, agar, agarose and carragenans, are neutral
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
discarded by the canning industries in Oregon, phobic and is insoluble in water and most
Washington, Virginia and Japan and by various organic solvents. It is soluble in hexafluoro-
finishing fleets in the Antarctic. Several coun- isopropanol, hexafluoroacetone, chloroalcohols
tries possess large unexploited crustacean re- in conjugation with aqueous solutions of miner-
sources, e.g. Norway, Mexico and Chile [25]. al acids [24] and dimethylacetamide containing
The production of chitosan from crustacean 5% lithium chloride. Chitosan, the deacetylated
shells obtained as a food industry waste is product of chitin, is soluble in dilute acids such
economically feasible, especially if it includes as acetic acid, formic acid, etc. Recently, the gel
the recovery of carotenoids. The shells contain forming ability of chitosan in N-methylmor-
considerable quantities of astaxanthin, a carot- pholine N-oxide and its application in controlled
enoid that has so far not been synthesized, and drug release formulations has been reported
which is marketed as a fish food additive in [30–32]. The hydrolysis of chitin with concen-
aquaculture, especially for salmon. trated acids under drastic conditions produces
To produce 1 kg of 70% deacetylated relatively pure D-glucosamine.
chitosan from shrimp shells, 6.3 kg of HCl and The nitrogen content of chitin varies from 5
1.8 kg of NaOH are required in addition to to 8% depending on the extent of deacetylation,
nitrogen, process water (0.5 t) and cooling whereas the nitrogen in chitosan is mostly in the
water (0.9 t). Important items for estimating the form of primary aliphatic amino groups.
production cost include transportation, which Chitosan, therefore, undergoes reactions typical
varies depending on labor and location. In India, of amines, of which N-acylation and Schiff
the Central Institute of Fisheries Technology, reaction are the most important. Chitosan de-
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-
4 M.N.V. Ravi Kumar / Reactive & Functional Polymers 46 (2000) 1 – 27

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, 1 H-
genation. The presence of the more or less NMR spectroscopy, 13 C 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
4.1. Physical and chemical characterization Chitosan molecular weight distributions have
been obtained using HPLC [46]. The weight-
The structural details of cellulose, chitin and average molecular weight (Mw ) of chitin and
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
properties are discussed in brief. Glycol chitin, a [h ] 5 KM a 5 1.81 3 10 23 M 0.93
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
4.1.1. Degree of N-acetylation chitosan lowers the molecular weight, changes
An important parameter to examine closely is the degree of deacetylation, and thereby alters
the degree of N-acetylation in chitin, i.e. the the charge distribution, which in turn influences
ratio of 2-acetamido-2-deoxy-D-glucopyranose the agglomeration. The weight-average molecu-
to 2-amino-2-deoxy-D-glucopyranose structural lar weight of chitin is 1.03310 6 to 2.5310 6 ,
units. This ratio has a striking effect on chitin but the N-deacetylation reaction reduces this to
solubility and solution properties. Chitosan is 1310 5 to 5310 5 [48].
M.N.V. Ravi Kumar / Reactive & Functional Polymers 46 (2000) 1 – 27 5

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

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) 2 , CaI 2 , CaBr 2 , CaCl 2 , etc. After this
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 2 (345 Pa). The fibres possessed a dull
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-
Chitin has been known to form microfibrillar sumers was also suggested. Clark and Smith
arrangements in living organisms. These fibrils reported a procedure for producing fibres by
are usually embedded in a protein matrix and dissolution of chitin at 958C in presaturated
have diameters from 2.5 to 2.8 nm. Crustacean solutions of lithium thiocyanate (saturated 608C)
cuticles possess chitin microfibrils with diame- [51]. No tensile properties or solution concen-
ters as large as 25 nm. The presence of mi- trations were reported. However, X-ray analysis
crofibrils suggests that chitin has characteristics showed a high degree of orientation. Solvent
which make it a good candidate for fibre removal was not successful even at 2008C.
spinning. To spin chitin or chitosan fibres, the Lithium iodide was implied to have behaved in
raw polymer must be suitably redissolved after the same manner. A ratio of 5 mol lithium
removal of extraneous material such as calcium thiocyanate per mole anhydroglucose unit was
carbonate and proteins, which encase the mi- found to exist. This is comparable to the
crofibrils. cellulose–lithium thiocyanate compound. Cellu-
lose solubility and the role of solvate / salt
5.2. Fibre formation — in retrospection complexes have been reviewed in detail [52,53].
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].
M.N.V. Ravi Kumar / Reactive & Functional Polymers 46 (2000) 1 – 27 7

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 3 –(NH 4 )OH
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 2 (710 Pa) and a breaking elongation of 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
mm 2 (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.
8 M.N.V. Ravi Kumar / Reactive & Functional Polymers 46 (2000) 1 – 27

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 2 pressure into acetone to form filaments. 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 2 (236–592 Pa) [66].
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
M.N.V. Ravi Kumar / Reactive & Functional Polymers 46 (2000) 1 – 27 9

coagulation studies were carried out but a clear 6.1. Photography


comparison could not be made. A problem with
this spin system is the removal and recovery of Chitosan has important applications in photo-
lithium from the fibre. The lithium acts as a graphy due to its resistance to abrasion, its
Lewis acid by solvating the chitin amide group. optical characteristics, and film forming ability.
It is unclear if this can be completely reversed Silver complexes are not appreciably retained
through washing, once the fibres are formed. by chitosan and therefore can easily be pene-
trated from one layer to another of a film by
5.3.3. Amine oxide /water system diffusion [70].
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 2 O), but no 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
10 M.N.V. Ravi Kumar / Reactive & Functional Polymers 46 (2000) 1 – 27

wound healing products are still at the early is accelerated by the oligomers of degraded
stages of research [84]. chitosan by tissue enzymes and this material
Sparkes and Murray [85] developed a sur- was found to be effective in regenerating the
gical dressing made of a chitosan–gelatin com- skin tissue in the area of the wound.
plex. The procedure involves dissolving the Biagini et al. [89] developed an N-carboxy-
chitosan in water in the presence of a suitable butyl chitosan dressing for treating plastic
acid, maintaining the pH of the solution at about surgery donor sites. A solution of N-carboxy-
2–3, followed by adding the gelatin dissolved in butyl chitosan was dialyzed and freeze-dried to
water. The ratio of chitosan and gelatin is 3:1 to produce a 1032030.5 cm 3 soft and flexible
1:3. To reduce the stiffness of the resulting pad, which was sterilized and applied to the
dressing a certain amount of plasticizers such as wound. This dressing could promote ordered
glycerol and sorbitol could be added to the tissue regeneration compared to control donor
mixture. Dressing film was cast from this sites. Better histoarchitectural order, better vas-
solution on a flat plate and dried at room cularization and the absence of inflammatory
temperature. It was claimed that, in contrast to cells were observed at the dermal level, while
conventional biological dressings, this ex- fewer aspects of proliferation of the malpighian
perimental dressing displayed excellent adhe- layer were reported at the epidermal level.
sion to subcutaneous fat. The British Textile Technology Group
Nara et al. [86] patented a wound dressing (BTTG) patented a procedure for making a
comprising a nonwoven fabric composed of chitin-based fibrous dressings [90–93]. In this
chitin fibres made by the wet spinning tech- method the chitin / chitosan fibres were not made
nique. In one of the examples, chitin powder by the traditional fibre-spinning technique and
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.
M.N.V. Ravi Kumar / Reactive & Functional Polymers 46 (2000) 1 – 27 11

Recently, Muzzarelli [94] introduced another for digestion of milk lactose. Cow’s milk con-
chitosan derivative, 5-methylpyrrolidinone tains only a limited amount of the NAG moiety,
chitosan, which is believed to be very promising hence some infants fed cow’s milk may have
in medical applications. This polymer is claimed indigestion. Many animals and some humans
to be compatible with other polymer solutions, (including the elderly) have similar lactose
including gelatin, poly(vinyl alcohol), poly- intolerances [96,97].
(vinyl pyrrolidone) and hyaluronic acid. The Animal nutritional studies have shown that
advantages include healing of wounded mensi- the utilization of whey may be improved if the
cal tissues, and of decubitus ulcers, depression diet contains small amounts of chitinous materi-
of capsule formation around prostheses, limita- al. This improvement is attributed to the change
tion of scar formation and retraction during in the intestinal microflora brought about by the
healing. Some wound-dressing samples were chitinous supplement [98]. Chickens fed a com-
prepared from an aqueous solution of this 5- mercial broiler diet containing 20% dried whey
methylpyrrolidone chitosan, which was dialyzed and 2 or 0.5% chitin had significantly improved
and laminated between stainless steel plates and weight again compared to controls [99,100].
freeze-dried to yield fleeces. The material could The feed efficiency ratio shifted from 2.5 to
be fabricated into many different forms, such as 2.38 due to incorporation of chitin in the feed
filaments, nonwoven fabrics, etc. Once applied [100].
to a wound, 5-methylpyrrolidinone chitosan
becomes available in the form of oligomers 6.5. Opthalmology
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
12 M.N.V. Ravi Kumar / Reactive & Functional Polymers 46 (2000) 1 – 27

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 Hg 21 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
concentration of Hg 21 and quantity of chitosan. chitosan a low affinity. Chitosan is versatile in
Jha et al. [104] studied the adsorption of sorbing metals and surfactants, as well as to
Cd 21 on chitosan powder over the concentration derivatization to attract basic dyes and other
range of 1–10 ppm using various particle sizes moieties (e.g., proteins from food processing
by adopting a similar procedure as for the plants).
removal of mercury. The sorption of dyes by chitosan is exother-
Hydroxymethyl chitin and other water-solu- mic, an increase in the temperature leads to an
ble derivatives are useful flocculents for anionic increase in the dye sorption rate, but diminishes
waste streams. Chitosan N-benzylsulfonate de- total sorption capacity [111]. However, these
rivatives were used as sorbents for removal of effects are small and normal wastewater tem-
metal ions in an acidic medium by Weltrowski perature variations do not significantly affect the
et al. [105]. The selective adsorption capacity overall decolorization performance [112]. Also,
for metal ions of amidoximated chitosan bead- the wastewater pH may be an important factor
g-PAN copolymer has been studied by Kang et in the sorption of certain dyes onto chitosan
al. [106]. These investigations clearly indicate because, at low pH, chitosan’s free amino
that chitosan has a natural selectivity for heavy groups are protonated, causing them to attract
metal ions and is useful for the treatment of anionic dyes. Contact time or, inversely, flux
wastewater. (wastewater flow per unit cross-sectional area)
McKay et al. [107] used chitosan for the affects sorption in a complex manner in a fixed
21 21 21 21
removal of Cu , Hg , Ni and Zn within bed design reactor system due to contact time,
the temperature range 25–608C at near neutral bed penetration and boundary layer effects. At
pH. Further adsorption parameters for the re- high flux, the diversion of liquid into larger
moval of these metal ions were reported by channels around particles and turbulent flow
Yang et al. [108]. Maruca et al. [109] used occur. In general, a low flux tends to give more
chitosan flakes of 0.4–4 mm for the removal of complete contaminant removal.
Cr(III) from wastewater. The adsorption capaci- For almost all the treatment strategies, a
ty increased with a decrease in the size of the major factor which has not yet been adequately
flakes, which implied that metal ions were characterized is the effect of typical wastewater
preferably adsorbed on the outer surface of contaminants on decolorization efficiencies. In
chitosan in the removal of Cr(III) from the typical dyeing systems it is well known that
wastewater. Pseudo-first-order kinetics are re- certain additives such as salt and surfactants can
ported. either accelerate or retard dye sorption pro-
cesses. The extreme variability of textile waste-
water must be taken into account in the design
6.6.2. Colour removal from textile mill of any decolorization system.
effluents Finally, a factor which significantly increases
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-
M.N.V. Ravi Kumar / Reactive & Functional Polymers 46 (2000) 1 – 27 13

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

release dosage forms enhance the safety, effica- tion in the stomach [133,134]. Also, chitosan
cy and reliability of drug therapy. They regulate matrix formulations appear to float and gradual-
the drug release rate and reduce the frequency ly swell in an acid medium. All these interesting
of drug administration to encourage patients to properties of chitosan make this natural polymer
comply with dosing instructions. Conventional an ideal candidate for controlled drug release
dosage forms often lead to wide swings in formulations. Many excellent reviews and books
serum drug concentrations. Most of the drug deal with the properties, chemistry, biochemis-
content is released soon after administration, try and applications of chitin, chitosan and their
causing drug levels in the body to rise rapidly, derivatives [1,4,54,72,73,75,135,136].
peak and then decline sharply. For drugs whose
actions correlate with their serum drug con- 6.9.1. Hydrogels based on chitin and chitosan
centration, the sharp fluctuations often cause Hydrogels are highly swollen, hydrophilic
unacceptable side-effects at the peaks, followed polymer networks that can absorb large amounts
by inadequate therapy at the troughs (Fig. 2) of water and drastically increase in volume. It is
[119]. well known that the physicochemical properties
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
M.N.V. Ravi Kumar / Reactive & Functional Polymers 46 (2000) 1 – 27 15

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


of b -chitin and poly(ethylene glycol) macromer
Semi-IPN polymer network hydrogels com-
posed of b-chitin and poly(ethylene glycol)
macromer were synthesized for biomedical ap-
plications [150,151]. The thermal and mechani-
cal properties of these hydrogels have also 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.
16 M.N.V. Ravi Kumar / Reactive & Functional Polymers 46 (2000) 1 – 27

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
M.N.V. Ravi Kumar / Reactive & Functional Polymers 46 (2000) 1 – 27 17

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

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.

Fig. 5. Preparation of MS (CM), MS (CML) and MS (CM) 6.9.3.4. Chitosan–polyethylene oxide


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
M.N.V. Ravi Kumar / Reactive & Functional Polymers 46 (2000) 1 – 27 19

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-
gram. interactions between alginate and chitosan at
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 2 is 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–CaCl 2 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-
20 M.N.V. Ravi Kumar / Reactive & Functional Polymers 46 (2000) 1 – 27

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
Fig. 7. Schematic representation of the ionic interactions between
observed that the device constructed with a
alginate and chitosan: (a) pH 5.4; (b) pH 2.0. chitosan membrane with a high crosslink den-
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
M.N.V. Ravi Kumar / Reactive & Functional Polymers 46 (2000) 1 – 27 21

regeneration reaction gives rise to various novel lated, and the self-defence function against
biofunctional macromolecular products having microbial infection was enhanced at the cellular
the original organization or new types of organi- level. On the basis of these results, several
zation. chitin and chitosan dressing materials (discussed
in the foregoing sections) have been developed
6.10.2. Cell-stimulating materials commercially for the healing treatment of
human and animal wounds.
6.10.2.1. In plants
Mainly two kinds of extracellular chitinase 6.10.3. Antibacterial agents
were found in the normal cell suspension cul- The growth of Escherichia coli was inhibited
ture of rice (Oryza sativa L. var. japonica cv. in the presence of more than 0.025% chitosan.
Koshihikari). In the presence of a chitin oligo- Chitosan also inhibited the growth of Fusarium,
saccharide mixture (degree of polymerization Alternaria and Helminthosporium. The cationic
2–8), however, the extracellular chitinase activi- amino groups of chitosan probably bind to
ty increased about three-fold over the control on anionic groups of these microorganisms, re-
secreting an additional extracellular new chitin- sulting in growth inhibition [189].
ase isoform. These three chitinase isoforms are
one group of pathogenesis-related (PR) proteins 6.10.4. Blood anti-coagulants ( heparinoids)
in plants [187]. Chitin and chitosan sulphates have blood
Soyabeans were coated with a thin layer of anticoagulant and lipoprotein lipase (LPL)-re-
depolymerized chitin, carboxymethyl (CM)- leasing activities. Chitin 3,6-sulfate showed
chitin and hydroxyethyl (HE)-chitin, and the about two-fold anticoagulant activity and 0.1-
seeds were cultured in the field. It was observed fold LPL-releasing activity over those of
that the seed chitinase increased 1.5–2.0-fold, heparin; the sulfate derivatives might be usable
the seed germination rate increased by 6%, the as heparinoids for artificial blood dialysis [187].
pod number increased by 9%, the plant dry
weight increased by 8%, and the crop yield also 6.10.5. Anti-throbogenic and haemostatic
increased by 10–12% over the control [188]. materials
Dressing with chitin films, sponges and fibres Chitosan fibres were found to be throm-
enhanced chitinase activity in tree-bark tissues bogenic and haemostatic in an in vitro test, and
around wounds up to four-fold over the control. N-hexanoyl and N-octanoyl chitosan fibres were
The chitin films, which were implanted in or anti-thrombogenic. Chitosan fibres can be used
used to dress the tree-bark tissues, were digested as haemostatic material; N-hexanoyl and N-
within 4 to 24 weeks thereafter and were octanoylchitosan fibres are used as anti-throm-
assimilated into the wounded bark tissues. The bogenic materials [190].
fate of N-acetyl-D-glucosamine in plant tissue is
unknown. Phenylalanine ammonia-lyase was 6.11. Chitosan as fat trapper
stimulated by treatment with chitin, and lignin
formation in the plant increased. As a result, One of the characters in a recent movie, ‘The
wound healing was accelerated [187]. Full Monty’, had a memorable line: ‘‘The less I
eat, the fatter I get.’’ Its a phenomenon that
6.10.2.2. In animals plagues many dieters who eat less and lose
Extracellular lysozyme activity was enhanced muscle instead of fat. As a result, their metabo-
in in vitro cultures of several mammalian cells lism slows down and it becomes more and more
by treatment with chitin and its derivatives. As a difficult to control weight. Fortunately, it is not
result, connective tissue formation was stimu- too difficult to lose the right stuff, fat, while
22 M.N.V. Ravi Kumar / Reactive & Functional Polymers 46 (2000) 1 – 27

improving muscle tone, metabolism and health. Kochi, India, for providing the sample of
Many supplements can help in the fat reduction chitosan. The author is grateful to the Council
process, including pyruvate and chitosan. Pyru- of Scientific and Industrial Research (CSIR),
vate, found in red apples, some types of cheese, Ministry of Human Resource Development
and red wine, stimulates fat loss and boosts Groups, Govt. of India, New Delhi, for financial
exercise performance. Chitosan attaches itself to assistance to carry out this research. The author
fat in the stomach before it is digested, thus is indebted to the referees for a thorough
trapping the fat and preventing its absorption by revision of the manuscript.
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 References
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