Journal of Controlled Release 75 (2001) 143–153
`
`www.elsevier.com/locate/jconrel
`
`Drug physical state and drug–polymer interaction on drug
`release from chitosan matrix films
`*
`b
`c
`S. Puttipipatkhachorn
`, J. Nunthanid , K. Yamamoto , G.E. Peck
`aFaculty of Pharmacy Mahidol University Bangkok
`Thailand
`bFaculty of Pharmacy Silpakorn University Nakhon Pathom
`Thailand
`cFaculty of Pharmaceutical Sciences Chiba University Chiba
`Japan
`dSchool of Pharmacy Purdue University West Lafayette IN
`USA
`
`a ,
`
`d
`
`-
`
`-
`
`Received 12 January 2001; accepted 9 May 2001
`
`Abstract
`
`Four different grades of chitosan varying in molecular weight and degree of deacetylation were used to prepare chitosan
`films. Salicylic acid and theophylline were incorporated into cast chitosan films as model acidic and basic drugs,
`respectively. Crystalline characteristics, thermal behavior, drug–polymer interaction and drug release behaviors of the films
`were studied. The results of Fourier transform infrared and solid-state C NMR spectroscopy demonstrated the drug–
`polymer interaction between salicylic acid and chitosan, resulting in salicylate formation, whereas no drug–polymer
`interaction was observed in theophylline-loaded chitosan films. Most chitosan films loaded with either salicylic acid or
`theophylline exhibited a fast release pattern, whereas the high viscosity chitosan films incorporated with salicylic acid
`showed sustained release patterns in distilled water. The sustained release action of salicylic acid from the high viscosity
`chitosan films was due to the drug–polymer interaction. The mechanism of release was Fickian diffusion control with
`subsequent zero order release. It was suggested that the swelling property, dissolution characteristics of the polymer films,
`pK of drugs and especially drug–polymer interaction were important factors governing drug release patterns from chitosan
`films. (cid:211) 2001 Elsevier Science B.V. All rights reserved.
`
`Keywords Chitosan films; Salicylic acid; Theophylline; Drug release; Drug–polymer interaction
`
`1. Introduction
`
`Chitosan, a cationic natural biopolymer produced
`from deacetylation of chitin, has been widely used
`for drug carrying devices in controlled drug delivery
`systems [1]. A drug–polymer dispersion can be
`utilized to accomplish coating of non-pariel seeds,
`
`*Corresponding author. Tel.: !66-2-644-8702/ !66-2-644-
`8677-91 ext. 1201; fax: !66-2-6448702.
`E-mail address pyspt@mahidol.ac.th (S. Puttipipatkhachorn).
`
`yielding a matrix for diffusion-mediated controlled
`drug release. In addition, a drug–polymer matrix film
`may be adaptable for transdermal drug delivery [2].
`The incorporation of a drug into a chitosan matrix to
`form a monolithic device can expand the use of this
`biopolymer. Up to date, the study of drug-loaded
`chitosan films were focused on release behavior of
`the drug from chitosan matrix films [3–6]. Depend-
`ing on the amount of chitosan [4], film thickness
`[4,5], and dissolution medium [4], the liberation of
`drug from the chitosan films varied from fast release
`
`0168-3659/01/$ – see front matter (cid:211) 2001 Elsevier Science B.V. All rights reserved.
`PII: S0168-3659( 01 )00389-3
`
`Mylan v. MonoSol
`IPR2017-00200
`MonoSol Ex. 2015
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`to slow release. In case of the sustained release, it
`was reported that the drug was released from the
`chitosan film following zero order [5] or first order
`kinetics [6]. Imai et al. [7] found the interaction of
`indomethacin with low molecular weight chitosan
`(MW 3800–25,000) and reported the improved
`release of the drug.
`Many grades of chitosan are available with differ-
`ent molecular weights and degree of deacetylation
`(%DD) [1,8]. In the previous paper, we studied the
`physicochemical characteristics of chitosan films
`prepared from four types of chitosan derived from
`crab shell chitin, that is, very low-viscosity grade
`(VL type, MW 50,000–60,000) with 82%DD; very
`low-viscosity grade (VL type, MW 50,000–60,000)
`with 100%DD; high-viscosity grade (H type, MW
`800,000–1,000,000) with 80–85%DD; and high-vis-
`cosity grade (H type, MW 600,000–800,000) with
`100%DD [9]. The characteristics of chitosan films
`prepared depended on its molecular weight and
`degree of deacetylation. Therefore, it is of interest to
`investigate the effect of molecular weight as well as
`degree of deacetylation of chitosan on the release
`behavior of drug from chitosan matrix films. In
`addition, drug physical state and molecular inter-
`action of drugs with chitosan of different grades in
`the films were also investigated using salicylic acid
`and theophylline as acidic and basic model drugs,
`respectively. Crystalline characteristics and thermal
`behavior of drugs in the chitosan films were studied
`by powder X-ray diffraction and differential scan-
`ning calorimetry. Fourier transform infrared (FTIR)
`13
`spectroscopy and solid-state
`C nuclear magnetic
`resonance
`(NMR)
`spectroscopy were used for
`characterization of the molecular interaction between
`drug and chitosan in the films. Finally, the relation of
`the molecular interaction of drug with chitosan to the
`drug release behavior from chitosan matrix film was
`discussed.
`
`2. Materials and methods
`
`Materials
`
`Four types of chitosan derived from crab shell
`chitin varying in molecular weight and degree of
`deacetylation (%DD) i.e. very low viscosity grade
`
`(VL type, MW 50,000–60,000) with 82%DD, very
`low viscosity grade (VL type, MW 50,000–60,000)
`with 100%DD and high viscosity grade (H type,
`MW 800,000–1,000,000) with 80–85%DD and high
`viscosity grade (H type, MW 600,000–800,000) with
`100%DD were given as gifts from Dainichiseika
`Colors and Chemicals Manufacturing, Japan. The
`H-type chitosan is a high viscosity grade (1000–
`2000 cps, 0.5% w/w in 1% w/w acetic acid solution
`at 20%C) where the VL-type chitosan is a very low
`viscosity grade (5$1 cps, 1% w/w in 0.5% w/w
`acetic acid solution at 20%C) (data obtained from the
`manufacturer). Salicylic acid was purchased from
`Nacalai Tesque, Japan. Theophylline USP (anhydr-
`ous) was purchased from Armend: Drug and Chemi-
`cal, USA. All other chemicals were of reagent grade.
`
`Preparation of drug-loaded chitosan films
`
`Salicylic acid or theophylline was either dissolved
`or dispersed in 1% w/w chitosan acidic solution at
`10–90% w/w drug loadings using 1% v/v acetic
`acid as a dissolving vehicle. The drug containing
`solution was then cast in a dish with a diameter of
`43.5 mm and dried at 60%C for 7–9 h.
`
`Morphology study
`
`The morphology of chitosan films loaded with
`salicylic acid or theophylline at various concen-
`trations was observed under a scanning electron
`microscope (model JSM 4510, Jeol, Japan). The
`samples were attached to the slab surfaces with
`double-sided adhesive tapes and then coated with
`gold to thickness about 30 nm under vacuum to
`make the samples conductive. Scanning electron
`photomicrographs were taken at appropriate magnifi-
`cation.
`
`Powder X-ray diffraction study
`
`Powder X-ray diffraction patterns of chitosan films
`loaded with various concentrations of salicylic acid
`or theophylline, pure drugs, and drug–polymer phys-
`ical mixtures were measured using powder X-ray
`diffractometer (model JDX-3530, Jeol, Japan) with
`Ni-filtered Cu radiation generated at 30 kV and 30
`mA as an X-ray source.
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`Differential scanning calorimetry DSC
`
`The DSC thermograms of pure drug and chitosan
`films loaded with salicylic acid at a concentration
`range of 10–90% w/w were recorded. The sample of
`2–4 mg was accurately weighed into a liquid
`aluminum pan with cover sealed. The measurements
`were performed under nitrogen purge over 50–200%C
`at a heating rate of 20%C/min.
`
`Fourier transform infrared FTIR
`spectroscopy
`
`Transmission infrared spectra of chitosan films
`loaded with various concentrations of salicylic acid
`or theophylline, pure drugs, and drug–polymer phys-
`ical mixtures were measured by using a Fourier
`transform infrared spectrophotometer (model Magna-
`IR! system 750, Nicolet, USA). The FTIR spectrum
`of a chitosan film prepared from VL-100%DD
`chitosan using salicylic acid as a dissolving vehicle
`was also measured. The powders were measured by
`KBr method and the films were directly measured for
`FTIR spectra.
`
`Nuclear magnetic resonance NMR
`spectroscopy
`
`13C NMR spectra of chitosan films loaded with
`10% salicylic acid or theophylline using acetic acid
`as a dissolving vehicle, pure drugs and a VL-
`100%DD chitosan film using salicylic acid as a
`dissolving vehicle were obtained by using the high
`13
`resolution solid-state C NMR spectrometer (model
`DPX-300, Bruker Switzerland). The spectra were
`recorded by means of the cross polarization-magic
`angle spinning (CP–MAS) method at 75.46 MHz
`13
`using a Bruker z-32DR C-MAS probe. The contact
`time for cross polarization was 1 ms. The 90% pulse
`13
`width was 5 ms and repetition time was 4 s. C
`chemical shifts were calibrated indirectly through the
`use
`of
`adamantane
`(29.5
`ppm from tetra-
`methylsilane).
`
`In vitro drug release study
`
`The release of salicylic acid or theophylline from
`10% drug-loaded chitosan films was evaluated using
`
`the USP dissolution apparatus V (paddle over disk,
`Pharmatest!, Germany)
`in distilled water. The
`paddles were rotated at 50 rpm at
`temperature
`32$0.5%C for transdermal drug delivery. Salicylic
`acid and theophylline (anhydrous) were analyzed by
`using a UV spectrophotometer (Perkin Elmer, Lam-
`bda 2). The analytical wavelength of salicylic acid
`and theophylline in distilled water were 296 nm and
`272 nm, respectively. All the experiments were done
`in triplicates.
`
`3. Results and discussion
`
`Morphology study
`
`The scanning electron photomicrographs of VL-
`82%DD chitosan films loaded with 30% and 40%
`salicylic acid are illustrated in Fig. 1. The drug
`crystals were observed at 40% drug loading (Fig. 1b)
`and they were clearly observed by visual inspection
`at higher
`than 40% drug loading.
`In the films
`prepared from VL-100%DD, H-80–85%DD, and H-
`100%DD chitosan, the drug crystals appeared at 50%
`drug loading and they were also observed by visual
`inspection at higher than 50% drug loading. The
`drug crystals were clearly observed in all types of
`chitosan films loaded with 10% theophylline and
`higher,
`indicating crystallization of
`theophylline
`during film formation. Two crystal forms of theo-
`phylline, needle-like and plate-like crystals were
`observed in all
`films. Rodriguez-Hornedo et al.
`[10,11] and Otsuka et al. [12] reported that
`the
`plate-like crystal was anhydrous crystal of theo-
`phylline, which would change to the needle-like
`crystal of monohydrate form in the presence of water
`or high humidity.
`It
`indicated that
`theophylline
`crystallized in anhydrous or monohydrate crystal
`forms when processing into chitosan films.
`
`Powder X-ray diffraction
`
`Powder X-ray diffraction patterns of 10–40%
`salicylic acid loaded in VL-82%DD chitosan films
`are shown in Fig. 2. The diffraction peaks associated
`with drug crystal molecules in VL-82%DD chitosan
`films were observed at 40% drug loading while those
`in the films prepared from VL-100%DD, H-80–
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`Fig. 1. Scanning electron photomicrographs of VL-82%DD
`chitosan films loaded with salicylic acid at different % drug
`loading, (a) 30%, and (b) 40%.
`
`Fig. 2. Powder X-ray diffraction patterns of VL-82%DD chitosan
`films loaded with salicylic acid (SA) at various % drug loading,
`(a) SA powder, (b) 40% SA film, (c) 30% SA film, (d) 10% SA
`film, and (e) VL-82%DD chitosan film.
`
`85%DD, and H-100%DD chitosan were observed at
`50% drug loading. The results indicated that salicylic
`acid molecule existed in an amorphous form or
`monomolecularly dispersed state in the VL-82%DD
`chitosan films at less than 40% drug loading and in
`VL-100%DD, H-80–85%DD,
`and H-100%DD
`chitosan films at less than 50% drug loading. The
`results were consistent with the data observed from
`SEM photomicrographs of chitosan films loaded with
`salicylic acid.
`The powder X-ray diffraction peaks of anhydrous
`theophylline in this study was assigned to the form II
`according to the Suzuki et al. study [13]. When
`
`into
`theophylline
`10–40% anhydrous
`loading
`chitosan films,
`the drug crystalline peaks were
`observed at 10% drug loading and higher (Fig. 3).
`The diffraction peaks associated with both anhydrous
`and monohydrate theophylline were observed as well
`as in VL-100%DD, H-80–85%DD, and H-100%DD
`chitosan films loaded with anhydrous theophylline. It
`seemed that theophylline in chitosan films existed in
`both anhydrous and monohydrate crystalline forms.
`There have been many studies reported the phase
`transition of hydrate and anhydrous theophylline
`[10–14]. Rodriguez-Hornedo et al. [10,11], Otsuka et
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`
`showed a sharp melting peak of salicylic acid
`powder at onset temperature of 157%C (Fig. 4). The
`drug melting peaks were observed at 40% drug
`loading and higher. In the other films prepared from
`VL-100%DD, H-80–85%DD and H-100%DD
`chitosan, the drug melting peaks were observed at
`50% drug loading and higher. The intensity and the
`sharpness of the endothermic peak increased with the
`increasing drug concentrations. The limiting percent
`of drug dissolved in films at its melting temperature,
`in other words, solid-state solubility, was determined
`from the y-intercept of the plot between the heat of
`melting (&Hm, J/g of drug) and the drug con-
`centration in film [17,18]. As a result, the solid-state
`solubility of salicylic acid in VL-82%DD chitosan
`film was estimated as 32% (Fig. 5). It indicated that
`salicylic acid molecules in the VL-82%DD chitosan
`films containing drug less than 40% existed in a
`dissolved state and at concentration higher than its
`
`Fig. 3. Powder X-ray diffraction patterns of VL-82%DD chitosan
`films loaded with theophylline (TH) at various % drug loading, (a)
`40%TH film, (b) 30%TH film, (c) 20%TH film, (d) 10%TH film,
`and (e) VL-82%DD chitosan powder. (A, anhydrous theophylline;
`M, theophylline monohydrate).
`
`al. [12,14] and Herman et al. [15] reported that the
`transformation of anhydrous theophylline to mono-
`hydrate form took place when being recrystallized
`from an aqueous buffer supersaturated solution or
`processed during wet granulation or even stored at
`high humidity condition. The phase transformation
`of theophylline monohydrate to anhydrous theophyl-
`line was about 60–70%C [16]. It was suggested that
`the crystallization below the phase transformation
`point would provide the monohydrate crystal. In this
`study, the chitosan films were dried at 60%C, which
`was closed to the transformation point. This may
`result in the crystallization of both anhydrous theo-
`phylline and theophylline monohydrate in the films.
`
`Differential scanning calorimetry
`
`DSC thermograms of VL-82%DD chitosan films
`loaded with salicylic acid at various concentrations
`
`Fig. 4. DSC thermograms of salicylic acid powder (SA), and
`VL-82%DD chitosan films loaded with salicylic acid at various %
`drug loading.
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`Fig. 5. Solubility of salicylic acid in chitosan films prepared from chitosan of different grades, (") VL-82%DD, (#) VL-100%DD, (!)
`H-80–85%DD, and (!) H-100%DD.
`
`chitosan film loaded with 10% salicylic acid is
`shown in comparison with chitosan free film, and
`salicylic acid powder in Fig. 6. The IR spectrum of
`chitosan showed the asymmetric and symmetric
`
`solid-state solubility the drug existed in crystalline
`form as well as in a dissolved state. The solid-state
`solubility of salicylic acid in films prepared from
`VL-100%DD, H-80–85%DD,
`and H-100%DD
`chitosan were estimated as 41%, 36%, and 44%,
`respectively.
`It was noted that
`the degree of
`deacetylation of chitosan affected the solid-state
`solubility of salicylic acid in chitosan films. As the
`degree of deacetylation increased the solid-state
`solubility increased. It might be attributed to the
`higher amino group content in chitosan with high
`degree of deacetylation that might
`interact with
`salicylic acid, resulting in increasing the solid-state
`solubility. Moreover,
`the influence of molecular
`weight of chitosan on the solid-state solubility was
`also observed. At
`the same range of degree of
`deacetylation,
`the solid-state solubility of drug in
`films slightly increased as the molecular weight of
`chitosan increased. This might be attributable to the
`difficulty of crystallization of drug in high molecular
`weight (high viscosity) chitosan during film forma-
`tion [19–21]. Consequently, the more dissolved state
`of drug was anticipated in the films obtained from
`high molecular weight chitosan solution, resulting in
`higher solid-state solubility value.
`
`Drug–polymer interaction
`
`Fourier transform infrared spectroscopy
`
`FTIR
`The transmission infrared spectra of VL-82%DD
`
`Fig. 6. Transmission infrared spectra of VL-82%DD chitosan
`films loaded with salicylic acid, (a) VL-82%DD chitosan film, (b)
`VL-82%DD chitosan film loaded with 10% salicylic acid, and (c)
`salicylic acid.
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`
`–1
`carboxylate anion stretching at 1565 cm and 1411
`–1
`cm , respectively,
`indicating that chitosan mole-
`cules in the free film was in the form of chitosonium
`acetate [9]. In the IR spectrum of salicylic acid, the
`carboxyl carbonyl stretching peak was observed at
`–1
`1656 cm [22]. When loading salicylic acid into
`chitosan film, changes in the IR spectrum were
`"1
`observed. The carbonyl stretching peak at 1655 cm
`(amide I peak), representing the N-acetyl functional
`group of chitosan disappeared and a new peak at
`"1
`1628 cm assigned to an asymmetric NH bending
`!
`3
`was observed [23]. The new peak was also observed
`"1
`at 1384 cm , which was assigned to the symmetric
`carboxylate anion stretching of salicylate anion.
`Similar IR spectra were observed in the salicylic
`acid-loaded chitosan films prepared from chitosan of
`the other grades. In order to clarify this change in IR
`peaks, the IR spectrum of VL-100%DD chitosan film
`using salicylic acid as a dissolving vehicle instead of
`acetic acid was measured. The spectrum was found
`to be similar to the spectra of all salicylic acid-
`loaded chitosan films using acetic acid as a dissolv-
`ing vehicle. It was therefore confirmed that salicylic
`acid might interact with chitosan at the position of an
`amino group to form salicylate salt. Furthermore, the
`IR spectra of the physical mixtures between salicylic
`acid and chitosan indicated no change in peaks of the
`drug and the polymer, suggesting no drug–polymer
`interaction in the physical mixtures. In addition, no
`change in the IR peaks of the drug and polymer was
`observed in all chitosan films loaded with theo-
`phylline as well as those in the drug–polymer
`physical mixtures.
`
`Nuclear magnetic resonance NMR
`spectroscopy
`13
`The C NMR spectra of chitosan films loaded
`with 10% salicylic acid are illustrated in Fig. 7. The
`resonances around 24, and 180 ppm were assigned to
`CH carbon and carbonyl carbon. These peaks
`3
`demonstrated that chitosan molecules existed in the
`form of chitosonium acetate as it had been reported
`in the Toffey et al. [24] and our previous studies [9].
`The resonances around 175 ppm might be assigned
`to a carbonyl carbon of salicylate group. It demon-
`strated the presence of salicylic acid in the form of
`salicylate salt, when loaded into the chitosan films.
`13
`The supportive data was shown by the C NMR
`spectra of salicylic acid, sodium salicylate, and VL-
`
`13
`Fig. 7. Solid-state C NMR spectra of 10% salicylic acid-loaded
`chitosan films prepared from chitosan of different grades, (a)
`VL-82%DD, (b) VL-100%DD, (c) H-80–85%DD, and (d) H-
`100%DD.
`
`100%DD chitosan film prepared by using salicylic
`acid as a dissolving vehicle instead of acetic acid
`(Fig. 8). The resonance at 173 ppm, assigned to
`COOH carbon of salicylic acid (Fig. 8c), would shift
`to more downfield at 176 ppm in the solid-state
`
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`13
`Fig. 8. Solid-state C NMR spectra of (a) VL-100%DD chitosan film prepared by using salicylic acid as a dissolving vehicle, (b) sodium
`salicylate, and (c) salicylic acid (data simulated by computer).
`
`NMR spectrum, assigned to COO carbon of salicyl-
`ate moiety in the chitosan films, and in sodium salt
`form (Fig. 8a and b) [21]. Though the resonances at
`174 ppm in chitosan films with lower degree of
`
`"
`
`deacetylation were associated with N-acetyl CO
`carbon of chitosan [24],
`this resonance could be
`assigned to COO carbon of salicylate salt form.
`Therefore, it may be concluded that salicylate salt
`
`"
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`
`formation might occur when loading the drug into
`chitosan films. In addition, no drug–polymer inter-
`13
`action was observed from the data of
`C NMR
`spectra of all chitosan films loaded with theophyl-
`line.
`
`In vitro drug release study
`
`The dissolution profiles of salicylic acid from 10%
`drug-loaded chitosan films into distilled water are
`illustrated in Fig. 9. The drug released rapidly from
`the VL-type chitosan films and reached 100% within
`1–1.5 h. In the case of the H-type chitosan films, the
`sustained release behavior was observed. The
`amount of drug released from H-80 to 85%DD and
`H-100%DD chitosan films during 24 h reached 95%
`and 74%, respectively. In addition, the release of
`theophylline from all chitosan films was fast release.
`We reported that VL-type chitosan films swelled and
`dissolved rapidly in distilled water [9]. The H-type
`chitosan films swelled extensively and slowly dis-
`solved with gradual erosion into small fragments,
`which could last in distilled water more than 24 h.
`The rapid drug release from VL-type chitosan films
`was attributed to the rapid dissolution of the polymer
`in distilled water even when there was the drug
`interaction between salicylic acid and chitosan. The
`sustained release action of salicylic acid from the
`H-type chitosan films was mainly due to the drug–
`
`Fig. 10. Fractional release of salicylic acid from 10% drug-loaded
`H-type chitosan films as a function of square root of time, (")
`VL-82%DD,
`(#) VL-100%DD,
`(!) H-80–85%DD,
`(!) H-
`100%DD.
`
`(
`
`polymer interaction since the slow dissolving of the
`H-type chitosan did not affect the drug release of
`theophylline. The release mechanism of salicylic
`acid from the H-type chitosan films up to 50–60%
`was Fickian following the exponential equation as
`1 / 2
`illustrated by M /M versus t
`plot and Higuchi’s
`t
`model (Fig. 10) [25,26]. The subsequent drug release
`higher than 60% was zero order release. The drug
`release from the H-100%DD chitosan film was
`slower than that from H-80 to 85%DD chitosan film.
`The H-80–85%DD chitosan film gave a much higher
`swelling index than the H-100%DD film [9], indicat-
`ing a more loose structure of the swollen film. The
`slower drug release from the H-100%DD films might
`be attributed to the denser and more viscous network
`of the swollen films as well as the higher amino
`content and thus more extensive drug–polymer
`interaction. It was suggested that the swelling prop-
`erty, the dissolution characteristics of the polymer
`films, the pK of the drug and the drug–polymer
`a
`interaction were important factors governing the drug
`release patterns from chitosan films.
`
`4. Conclusion
`
`Fig. 9. Dissolution profiles of salicylic acid from 10% drug–
`loaded chitosan films prepared from chitosan of different grades in
`distilled water. Each data represents mean$S.D. of three de-
`terminations (n#3), (") VL-82%DD, (#) VL-100%DD, (!)
`H-80–85%DD, and (!) H-100%DD.
`
`Physicochemical characterization of all chitosan
`films loaded with salicylic acid and theophylline
`could reveal the drug physical state and drug–poly-
`mer interaction. The solid-state solubility of salicylic
`
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`its
`acid in chitosan films was about 32–44% at
`melting temperature. The higher
`the molecular
`weight and degree of deacetylation of chitosan the
`higher the solid-state solubility was. The drug ex-
`isted in an amorphous state or monomolecularly
`dispersed in the films like solid-state solution when
`loaded at concentration less than its solid-state
`solubility. Theophylline existed in both monohydrate
`and anhydrous forms in all chitosan films. The data
`13
`of FTIR and solid-state
`C NMR spectroscopy
`demonstrated the drug–polymer interaction between
`salicylic acid and chitosan at an amino group,
`resulting in salicylate formation, whereas no drug–
`polymer interaction was observed in theophylline-
`loaded chitosan films. The drug–polymer interaction
`affected the release of salicylic acid from the high
`viscosity chitosan films resulted in sustained release
`action. It was summarized that chitosan could inter-
`act with negatively charged (acidic) drugs when
`incorporated into films and this might affect the drug
`release characteristics as well as the physicochemical
`property of the drug and polymer.
`
`Acknowledgements
`
`The authors wish to thank Dainichiseika Colors
`and Chemicals Manufacturing, Japan, who kindly
`provided the chitosan. We would like to acknowledge
`National Metal and Materials Technology Center
`(MTEC) of Thailand for supporting powder X-ray
`13
`diffractometer
`and solid-state
`C NMR spec-
`trophotometer. We also wish to thank Associate
`Professor Dr Duangdeun Meksuriyen, Department of
`Biochemistry, Faculty of Pharmaceutical Sciences,
`Chulalongkorn University, Thailand, for her sug-
`gestions in the NMR study.
`
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`Vgmk 66
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`