喷雾干燥法制备微胶囊方法

Journal of Microencapsulation,June2005;22(4):377–395
Preparation of cross-linked chitosan microspheres
by spray drying:Effect of cross-linking agent on the properties of spray dried microspheres
K.G.H.DESAI1&H.J.PARK1,2
1School of Life Sciences and Biotechnology,Korea University,Sungbuk-ku,Seoul,South Korea,
and2School of Life Sciences and Biotechnology,Korea University and Department of Packaging Science,Clemson University,Clemson,SC,USA
(Received4September2004;accepted10December2004)
Abstract
Chitosan microspheres cross-linked with three different cross-linking agents viz,tripolyphosphate (TPP),formaldehyde(FA)and gluteraldehyde(GA)have been prepared by spray drying technique. The influence of these cross-linking agents on the properties of spray dried chitosan microspheres was extensively investigated.The particle size and encapsulation efficiencies of thus prepared chitosan microspheres ranged mainly between4.1–4.7m m and95.12–99.17%,respectively.Surface morphol-ogy,%erosion,%water uptake and drug release properties of the spray dried chitosan micro-spheres was remarkably influenced by the type(chemical or ionic)and extent(1or2%w/w)of cross-linking agents.Spray dried chitosan microspheres cross-linked with TPP exhibited higher swelling capacity,%water uptake,%erosion and drug release rate at both the cross-linking extent (1and2%w/w)when compared to those cross-linked with FA and GA.The sphericity and surface smoothness of the spray dried chitosan microspheres was lost when the cross-linking extent was increased from1to2%w/w.Release rate of the drug from spray dried chitosan microspheres decreased when the cross-linking extent was increased from1to2%w/w.The physical state of the drug in chitosan-TPP,chitosan-FA and chitosan-GA matrices was confirmed by the X-ray diffrac-tion(XRD)study and found that the drug remains in a crystalline state even after its encapsulation. Release of the drug from chitosan-TPP,chitosan-FA and chitosan-GA matrices followed Fick’s law of diffusion.
Keywords:Chitosan microspheres,spray drying,tripolyphosphate,formaldehyde,gluteraldehyde,swelling, erosion,sustained release
Introduction
There has been considerable interest in recent years in developing controlled or sustained drug delivery systems by using biopolymers.Controlled or sustained release drugs provide many advantages in comparison with conventional forms:reduced side effects,drug Correspondence:Professor H.J.Park,307,School of Life Sciences and Biotechnology,Korea University,1,5-Ka,Anam-Dong, Sungbuk-ku,Seoul-136-701,South Korea.Tel:82232903450.Fax:8229535892.E-mail:hjpark@korea.ac.kr
ISSN0265-2048print/ISSN1464-5246online#2005Taylor&Francis
DOI:10.1080/02652040500100139
378K.G.H.Desai&H.J.Park
concentration kept at effective levels in plasma and improved utilization of drug and decrease the dosing times(Kim et al.2002).Of the different drug delivery systems,nano or microparticles based drug delivery systems gained significant importance(Ravi Kumar 2000).With the attractive properties and wider application range,they occupy unique position in drug delivery technology(Ravi Kumar2000).The use of microspheres-based therapy allows drug release to be carefully tailored to the specific treatment site through the choice of appropriate formulation ing innovative microencapsulation technologies and by modifying the polymeric matrix,microspheres can be developed into an optimal drug delivery system which will provide desired release profile(Benita1996; Ravi Kumar2000).
Chitosan,a natural biopolyaminosaccharide,is obtained by alkaline deacetylation of chitin that is found widely in nature.Chitosan has attracted significant interest in recent years.This is largely due to the proposed novel application of the polymer in phar-maceutical,food and various industrial and biotechnological fields.These applications are possible because of the polymer reactive groups and their biodegradability,low toxicity and biocompatibility(Hejazi and Amiji2003).Due to the easy availability of free amino groups in chitosan,it carries a positive charge and,thus,in turn reacts with many negatively charged surfaces/polymers(Ko et al.2002).This principle has been used for the produc-tion of chitosan microcapsules and microspheres to control drug release(Hejazi and Amiji2003).Chitosan microspheres are most widely studied drug delivery systems for the controlled release of drugs viz.antibiotics,anti-hypertensive agents,anti-cancer agents, anti-inflammatory agents,proteins,peptide drugs and vaccines(Sinha et al.2004). Chitosan microspheres can be synthesized by a number of different techniques such as solvent evaporation,spray drying,coacervation,emulsification/internal gelation and suspen-sion cross-linking(Sinha et al.2004).
Although numerous techniques are available for the synthesis of microparticles,spray drying technique is widely used in the pharmaceutical industries because of its numerous advantages over other methods.The advantage of spray drying technique for applica-tion to microencapsulation is that it is reproducible,rapid and easy to scale up(Masters 1991;Benita1996;He et al.1999;Sinha et al.2004).Spray drying technique can be used to produce dry powders,granules or agglomerates from drug-excipient solutions and suspensions(Wang and Wang2002).The particle size of the microparticles prepared by spray drying technique ranged from microns to several tens of microns and had a relatively narrow distribution(Masters1991).Recently,a number of articles have been published describing the preparation of controlled release microparticles by such a spray drying tech-nique.For example,microparticles composed of the water soluble polymers used as the carrier for intra-articular delivery of dexamethasone(Pavenetto et al.1994)or sustained release dosage form(Maa and Prestrelski2000)for the delivery of acetazolaminde (Di Martino et al.2001),butorophanol(Chang and Li2000),dexamethasone hydrochloride and toremifene citrate(Kortesuo et al.2000),erythromycin and clarithromycin(Zgoulli et al.1999).Water insoluble polymer polylactic acid or poly(lactide co-glycolide)was prepared for the delivery of rifampicin(Bain et al.1999a,b,O’Hara and Hickey2000) and gentamycin(Prior et al.2000).
Ideally,a delivery system might be developed to release a drug at precisely the rate it is required for different application.Chitosan-based microspheres have been prepared by spray drying technique(He et al.1999;Huang et al.2002;2003a,b;Filipovic-Grcic et al. 2003).However,as an unfavourable factor,spray dried chitosan microspheres swell quickly in water and release the encapsulated drug immediately(Genta et al.1995).The drug release kinetics from spray dried chitosan microspheres is affected by the concentration
Preparation of cross-linked chitosan microspheres379 and molecular weight of the chitosan,solubility of the drugs,especially the chitosan matrix(cross-linked or non-cross-linked)(He et al.1999).Therefore,non-cross-linked spray dried chitosan microspheres are unsuitable for sustained drug delivery(Genta et al. 1995;He et al.1999).In order to stabilize the spray dried chitosan microspheres,cross-linking agents such as GA and FA have been used(He et al.1999).In an earlier work (Desai and Park2005),TPP has been demonstrated as a new stabilizing agent for the preparation of chitosan microspheres by spray drying technique covering the influence of concentration and molecular weight of the chitosan and drug loading on the properties of spray dried chitosan-TPP microspheres.However,the effect of different cross-linking agents on the properties of spray dried chitosan microspheres is not studied so far.
In continuation of the ongoing programme of research to develop the chitosan based microspheres for the release of drugs(Ko et al.2002;Lee et al.2003),one now reports the influence of three different cross-linking agents(TPP,FA and GA)on the proper-ties(%encapsulation efficiency,size,surface morphology,%erosion,%swelling and release behaviour)of spray dried chitosan microspheres.Therefore,the objective of the pre-sent study was to prepare the chitosan-TPP,chitosan-FA and chitosan-GA microspheres by spray drying technique through a novel process as well as to examine the influence of the above mentioned three different cross-linking agents on the properties of thus prepared microspheres.Acetaminophen was used as a model drug candidate.
Materials and methods
Materials
Acetaminophen(99.5%purity)was purchased from Kanto Chemical Co.,Inc.(Tokyo, Japan).Chitosan(medium molecular weight)was purchased from Sigma-Aldrich Chemie (Steinheim,Germany).The average molecular weight of chitosan was determined by batch mode method using multi-angle laser light scattering(MALLS)photometer according to the method of Chen and Tsaih(1998).The average molecular weight of the chitosan was found to be1.336Â106.The%N-deacetylation of chitosan was determined by the 1NMR spectroscopy method(Hirai et al.1991;Lavertu et al.2003).The degree of
deacetylation of the chitosan was found to be82.10%.FA(35%)and GA(25%)were purchased from Showa Chemicals(Japan).All other chemicals were of analytical grade and used as received.Ultrapure water(Millipore,USA)water was used throughout the study.
Preparation of cross-linked chitosan microspheres by spray drying
Model drug,acetaminophen(0.5%w/v)was dissolved in300ml of1%v/v acetic acid solution.Then the chitosan was dissolved in the drug solution by stirring it overnight.About 10ml of different cross-linking agents(see Table I)(TPP or GA or FA)was added dropwise into the aqueous chitosan-drug solution with constant stirring at8000rpm for30min using a Young Ji HMZ20DN stirrer(Hana Instruments).Thus prepared chitosan-TPP-drug or chitosan-GA-drug or chitosan-FA-drug solution was then spray dried to obtain the cross-linked chitosan microspheres loaded with the drug.Spray drying was performed using a SD-05spray drier(Lab Plant,UK),with a standard0.5mm nozzle.Spray drying conditions such as inlet temperature,liquid flow and drying air flow were set at170 C, 2ml minÀ1,1.2m3minÀ1,respectively.The atomizing air pressure was60kPa.When the liquid was fed to the nozzle with peristaltic pump,atomization occurred by the force of the compressed air,disrupting the liquid into small droplets.The droplets,together with
hot air,were blown into a chamber where the solvent in the droplets was evaporated and discharged out through an exhaust tube.The dry product was then collected in a collection bottle.The preparation process of cross-linked chitosan microspheres through a novel process by spray drying method is shown in Figure 1.
Loading efficiency
About 10mg of drug-loaded chitosan-TPP or chitosan-GA or chitosan-FA micro-spheres were dissolved in 50ml of 0.1N HCl.The solution was passed through
Table I.Preparation of crosslinked chitosan microspheres by spray drying method.
Formulation code Chitosan concentration (%w/v)Chitosan
molecular weight
Cross-linking agent Cross-linking extent (%w/w)Drug loading (%w/v)F1
1.0 1.336Â106Tripolyphosphate 10.5F2
1.0 1.336Â106Tripolyphosphate 20.5F3
1.0 1.336Â106Formaldehyde (35%)10.5F4
1.0 1.336Â106Formaldehyde 20.5F5
1.0 1.336Â106Gluteraldehyde (25%)10.5F6 1.0 1.336Â106Gluteraldehyde 20.5
Spray dried chitosan-TPP or chitosan-FA or chitosan-GA
microspheres loaded with acetaminophen
Figure 1.Preparation process of cross-linked chitosan microspheres by spray drying.
380K.G.H.Desai &H.J.Park
a0.22m m membrane filter(Millipore,USA)and then the drug content was assayed by measuring the absorbance at201nm( max of acetaminophen in0.1N HCl)after suitable dilution using UV spectrophotometer(Shimadzu1601PC,Japan).Experiments were performed in triplicate(n¼3)and loading efficiencies were calculated using equation(1).
Loading efficiencyð%Þ¼Calculated drug concentration
Theoretical drug concentration
Â100ð1Þ
Measurement of particles size
Spray dried chitosan microspheres exhibited quick swelling in liquid medium and,hence, sizes could not be determined using a laser diffraction technique in a particle size analyser. Therefore,the particle size was determined by microscopy.Briefly,$5mg of cross-linked chitosan microspheres were taken on a glass slide and sizes of$200spherical particles were measured each time(n¼3)by using a biological microscope(Olympus,Japan).
Erosion study
Spray dried placebo chitosan-TPP,chitosan-FA and chitosan-GA microspheres(200mg) were immersed in phosphate buffer solution(pH7.4)and stirred at100rpm for6h. After6h,microspheres were separated by centrifuge(3000rpm,10min)and dried in a temperature controlled oven(JEIO TECH,FO600M,South Korea)at40 C for24h to dry the microspheres completely;these were weighed to calculate the mass loss. Surface morphology
The surface morphology of the spray dried chitosan microspheres cross-linked with TPP, FA and GA was examined by means of Hitachi(Japan)scanning electron microscope.The powders were previously fixed on a brass stub using double-sided adhesive tape and then were made electrically conductive by coating,in a vacuum,with a thin layer of platinum ($3–5nm),for100s and at30W.The pictures were taken at an excitation voltage of15kv and a magnification of1.8,2,3.5,4,4.5or800k.
Swelling study
The dynamic swelling properties of the spray dried chitosan-TPP,chitosan-FA and chitosan-GA microspheres in the dissolution medium(phosphate buffer solution,pH7.4) were determined.Spray dried chitosan-TPP,chitosan-FA and chitosan-GA microspheres of known weight(200mg)without containing the drug were placed in phosphate buffer solution(pH7.4)for a period of6h.The swollen chitosan-TPP,chitosan-FA and chitosan-GA microspheres were collected by a centrifuge and the wet weight of the swollen microspheres was determined by first blotting the particles with filter paper to remove absorbed water on surface and then weighing immediately on an electronic balance. The weight of the swollen microspheres was determined at a pre-determined time period (0.5,1,2,4and6h)to accuracy of0.01mg using an electronic balance.The percentage
Preparation of cross-linked chitosan microspheres381
of swelling of the cross-linked spray dried chitosan microspheres in the dissolution media was then calculated using equation(2).
S SW¼
W tÀW o
W o
Â100ð2Þ
where S SW is the percentage of swelling of spray dried chitosan-TPP or chitosan-FA or chitosan-GA microspheres,W t denotes the weight of the spray dried microspheres at time t and W o is the initial weight of the microspheres.Equilibrium water uptake(%water uptake)of the cross-linked chitosan microspheres(placebo)were also determined by measuring the extent of swelling of the matrices in phosphate buffer solution(pH7.4). To ensure complete equilibrium,the samples were allowed to swell for24h.
X-ray diffraction
The physical state of the model drug(acetaminophen)in the spray dried chitosan-TPP, chitosan-FA and chitosan-GA matrices was assessed by XRD studies.X-ray powder diffraction patterns of neat acetaminophen,spray dried placebo chitosan microspheres and chitosan-TPP,chitosan-FA and chitosan-GA microspheres loaded with drug were obtained at room temperature using a Philips X’Pert MPD diffractometer(Philips,The Netherlands) with Co as anode material and graphite monochromator operated at a voltage of40kV. The samples were analysed in the2 angle range of2–60 and the process parameters were set as scan step size of0.025 (2 ),scan step time of1.25s and time of acquisition of1h. In vitro drug release
The in vitro release of the model drug(acetaminophen)from spray dried chitosan-TPP, chitosan-FA and chitosan-GA microspheres was determined using a dissolution apparatus (TW-SM,Wooju Scientific,Co.,Korea).In order to suspend the spray dried chitosan microspheres in the dissolution medium,25mg of microspheres were taken into the previously soaked cellulose dialysis bag(molecular weight cut-off8000)containing3ml of dissolution media and tied to the paddle.The in vitro release studies of acetaminophen were carried out at paddle rotation of100rpm in900ml of phosphate buffer solution (pH7.4and37 C).An aliquot of the release medium(5ml)was withdrawn through a sampling syringe attached with0.22m m membrane filter(Millipore,USA)at pre-determined time intervals(0.5,1,2,3,4,5and6h)and an equivalent amount of fresh dissolution medium which was pre-warmed at37 C was replaced.Collected samples were then analysed for acetaminophen content by measuring the absorbance at202nm ( max of acetaminophen in phosphate buffer solution(pH7.4))after suitable dilution using UV spectrophotometer(Shimadzu1601PC,Japan).In vitro release studies were performed in triplicate(n¼3)for each microsphere formulation in an identical manner. Results and discussion
Preparation of cross-linked chitosan microspheres by spray drying
Chitosan is currently receiving a great deal of interest in pharmaceutical applications. The main reasons for this increasing attention are certainly its interesting intrinsic properties.Spray drying is a well-known process,which is used to produce dry powders, granules or agglomerates from drug excipient solutions and suspensions(He et al.1999). 382K.G.H.Desai&H.J.Park
Recently,a number of articles have been published describing the preparation of chitosan microspheres by such a spray drying method(Genta et al.1995;He et al.1999; Huang et al.2002;2003a,b;Filipovic-Grcic et al.2003).The drug release kinetics from chitosan microspheres is affected by the concentration and molecular weight of the chitosan,solubility of the drug and encapsulating process,especially the cross-linked chitosan matrix density(Sinha et al.2004).Non-cross-linked spray dried chitosan microspheres cannot be kept suspended in water because of swelling and dissolution. As a result,the release rate of the drug from non-cross-linked spray dried chitosan microspheres is rapid(more than90%of the drug release within0.5h)(Genta et al.1995). Therefore,non-cross-linked spray dried chitosan microspheres are unsuitable for the sustained release application.To date,the most common cross-linkers used with chitosan are chemical cross-linking agents(FA and GA)and ionic cross-linking agents(genipin, TPP).Their reaction with chitosan is well-documented(Berger et al.2004).More recently, TPP has been demonstrated as a new stabilizing agent for the preparation of chitosan microspheres by spray drying method(Desai and Park2005).However,comparative study, i.e.the influence of different cross-linking agents(TPP,FA and GA)on the properties of spray dried chitosan microspheres is not studied so far.Therefore,this paper reveals their effects on the size,%encapsulation efficiency,%swelling,%erosion,surface morphology and release behaviour of the spray dried chitosan microspheres.Thus,cross-linked chitosan microspheres by spray drying method were prepared as an effort to explore the possibility of them being used as sustained release carriers for drugs.
Properties of spray dried chitosan-TPP,chitosan-FA and chitosan-GA microspheres
The properties of spray dried chitosan microspheres(yield,mean size and encapsulation efficiency)loaded with the drug are presented in Table II.The yield(%)of the spray dried chitosan microspheres cross-linked with different cross-linking agents ranged mainly between39.3–45.8%.Generally,yield of the microspheres prepared by the spray drying method depends upon the spray drying conditions(inlet temperature,flow rate and compressed air flow).Under the present spray drying conditions,yield of drug loaded chitosan microspheres did not vary much with the varying amount of different cross-linking agents.The particle size of the spray dried chitosan microspheres cross-linked with TPP, FA and GA ranged between4.1–4.7m m.However,the particle size decreased slightly(see Table II)when the cross-linking extent of TPP,FA and GA increased from1to2%w/w. Generally,the spray dried chitosan-TPP,chitosan-FA and chitosan-GA microspheres could be produced with higher(95.12–99.17%)encapsulation efficiencies.However,as the Table II.Results of mean particle size,%encapsulation efficiency,%yield,%erosion and%water uptake of spray dried chitosan-TPP(F1and F2),chitosan-FA(F3and F4)and chitosan-GA(F5and F6)microspheres (Values are expressed as meanÆstandard deviation).
Formulation code
Mean
particle size(m m)
Encapsulation
efficiency(%)
Yield
(%)%Erosion
%Water
uptake
F1 4.5Æ0.899.17Æ1.041.210.1Æ1.4365.2Æ11.3 F2 4.1Æ0.596.42Æ1.443.58.8Æ1.1340.3Æ5.3 F3 4.7Æ0.799.03Æ1.340.4 6.8Æ1.3312.6Æ4.8 F4 4.3Æ0.395.12Æ0.639.3 5.1Æ0.7295.8Æ7.6 F5 4.6Æ0.898.81Æ1.145.8 3.7Æ0.8266.2Æ4.6 F6 4.2Æ0.495.61Æ1.242.6 2.9Æ0.6245.2Æ8.1
Preparation of cross-linked chitosan microspheres383
384K.G.H.Desai&H.J.Park
cross-linking extent of TPP,FA and GA increased from1to2%w/w,the encapsulation efficiencies of spray dried chitosan microspheres decreased slightly(see Table II). Surface morphology
The surface morphologies of spray dried chitosan-TPP,chitosan-FA and chitosan-GA microspheres are shown in Figures2and 3.The new process of preparation of chitosan-TPP,chitosan-FA and chitosan-GA microspheres by spray drying method produced the microspheres with spherical shape and smooth surface.However,well-defined change in the surface morphology of spray dried chitosan microspheres was observed when the cross-linking extent of TPP,FA and GA was increased from1to2%w/w. For instance,microspheres cross-linked with1%w/w of TPP or FA or GA were completely spherical and had a smooth surface(see Figure2(a,b and c)).Whereas,in the case of microspheres cross-linked with2%w/w of TPP or FA or GA,although the microspheres were spherical,but had a depressed(wrinkles)surface.However,spray dried chitosan microspheres prepared with FA or GA had more depressed surfaces(see Figure3(b and c)) than those prepared with TPP(Figure3(a)).The pictures of the SEM study revealed that chemical cross-linking(GA or FA)had a remarkable effect on the surface morphology of spray dried chitosan microspheres than the ionic cross-linking(TPP).On the other hand, drug(acetaminophen)crystals were adhered to the surface of the spray dried chitosan microspheres due to its extreme crystalline nature.
Erosion of matrices
The chitosan microspheres prepared by cross-linking with different cross-linking agents are stirred in dissolution media(phosphate buffer,pH7.4)for6h.These results,given in Table II,indicate that erosion decreases with an increase in cross-linking of the matrices. Among the three cross-linking agents used,GA-cross-linked microspheres show the least erosion,i.e.2.9–3.7%,but the FA-and TPP-cross-linked microspheres show erosions of5.1–6.8%and8.8–10.1%,respectively.The percentage erosion of TPP-cross-linked microspheres is higher than the FA-and GA-cross-linked matrices because the latter cases involves actual chemical reactions between FA or GA and chitosan and,therefore, FA-chitosan or GA-chitosan is a stronger and more rigid matrix than the ionically(TPP) cross-linked matrix.The surface morphology of spray dried chitosan-TPP,chitosan-FA and chitosan-GA microspheres after their erosion study was also examined by SEM and the same are presented in Figure4.It can be seen that the chitosan-TPP microspheres (Figure4(a))did not maintain the form of sphere indicating the poor rigidity of the spray dried chitosan-TPP matrix.Spray dried chitosan-FA(Figure4(b))and chitosan-GA (Figure4(c))microspheres maintained their spherical shape even after6h,indicating the more rigidity of the chitosan-FA and chitosan-GA matrices.
Swelling behaviour
It is not known whether the macro-molecular chains of polymer are fixed by ionic cross-linking or chemical cross-linking,the swelling ability of the polymer decreases. However,the swelling ability of spray dried chitosan is higher than the pure chitosan (Mi et al.1999).The swelling experiments of spray dried chitosan-TPP,chitosan-FA and chitosan-GA microspheres were conducted in dissolution media(pH7.4).The swelling capacity(%)of spray dried chitosan microspheres cross-linked with different cross-linking
agents (TPP,FA and GA)increased with time.The influence of different cross-linking agents (TPP,FA and GA)at a cross-linking extent of 1and 2%w/w on the swelling behaviour of spray dried chitosan microspheres is depicted in Figures 5and 6,respectively.From Figures 5and 6,it is very clear that the swelling capacity of the cross-linked
spray Figure 2.Scanning electron microscopic pictures of spray dried chitosan microspheres cross-linked with 1%w/w TPP (a),FA (b)and GA (c).
Preparation of cross-linked chitosan microspheres 385
dried chitosan microspheres was influenced by the nature of the cross-linking,i.e.chemical or ionic cross-linking.For instance,spray dried chitosan microspheres cross-linked with FA or GA (chemical cross-linking)exhibited lower swelling capacity when compared to those cross-linked with TPP (ionic cross-linking)(see Figures 5and 6).Depending on the
nature Figure 3.Scanning electron microscopic pictures of spray dried chitosan microspheres cross-linked with 2%w/w TPP (a),FA (b)and GA (c).
386K.G.H.Desai &H.J.Park
of the cross-linkers (chemical or ionic cross-linking agents),the main interactions forming the network are covalent or ionic bonds (Berger et al.2004).In the case of chemical cross-linking,the aldehyde groups form covalent imine bonds with the amino groups of chitosan,due to resonance established with adjacent double ethylenic bonds via a Schiff
reaction Figure 4.Scanning electron microscopic pictures of spray dried chitosan-TPP (a),chitosan-FA (b)and chitosan-GA microspheres after their erosion study (cross-linking extent 1%w/w).
(Berger et al.2004).These aldehydes allow direct reaction in aqueous media,under mild conditions with or without the addition of auxiliary molecules such as reducers (Monteiro and Airoldi 1999;Berger et al.2004).Ionic interactions between the negative charges of the cross-linker (TPP)and positively charged groups of chitosan are the main interactions inside the network.Therefore,chemically cross-linked (covalent)chitosan matrices are more rigid and,hence,these (chitosan-FA and chitosan-GA)matrices exhibited lower swelling capacity (lower water uptake (see Table II))than the ionically cross-linked (chitosan-TPP)matrix.On the other hand,as the extent of cross-linking increased from 1to 2%w/w,the swelling capacity of the spray dried chitosan microspheres decreased considerably.These results sup-port that the more tightly cross-linked chitosan-TPP or chitosan-FA or chitosan-GA matrix does not swell (lower water uptake (see Table II))as much as the loosely cross-linked chitosan-TPP or chitosan-FA or chitosan-GA matrix.At lower levels of TPP or FA or GA (i.e.lower cross-link density),the network is loose and has a high hydrodynamic free volume to accommodate more of the solvent molecules,thereby inducing chitosan-TPP or chitosan-FA or chitosan-GA matrix swelling.The water uptake in hydrogels depends upon the extent of hydrodynamic free volume and availability of hydrophilic functional groups for the water to establish hydrogen bonds.Higher water uptake values were observed at lower levels of crosslinking (see Table II)and vice versa observed in the present study confirm the formation of rigid chitosan-TPP or chitosan-FA or chitosan-GA networks through a new process due to
cross-linking.
100
200
3000.512
46
Time (h)
S w e l l i n g (%
)
TPP
FA GA
Figure 5.The influence of 1%w/w TPP,FA and GA on the swelling behaviour of spray dried chitosan microspheres.。