Effect of ionic crosslinking on the drug release properties of chitosan diacetate matrices

Article abstract of DOI:10.1002/jps.20764

Chitosan diacetate (CDA) was prepared by alkylating the amino moieties of chitosan with mono-iodoacetic acid. Subsequently, CDA was cross-linked with Al³⁺, Zn²⁺, and Ca²⁺ ions to yield three ionotropically crosslinked polymeric matrices. These composite matrices were characterized employing infrared spectroscopy (IR) and differential scanning calorimetry (DSC). Subsequently, they were loaded with caffeine, as a model drug, and were assessed as sustained release carriers by evaluating their caffeine release profiles. Interestingly, only CDA-Zn²⁺ complex sustained the release of caffeine effectively in a zero-order manner. The drug release and thermal behavior of the tested matrices agree with the relative strength of the ionic or coordination character of the bonds. This, in turn, depends on the position of the complexing ions on the electrophilic softness/hardness scale.

Full text of DOI:10.1002/jps.20764

COMMUNICATION
Effect of Ionic Crosslinking on the Drug Release Properties of
Chitosan Diacetate Matrices
KHALED M. AIEDEH, MUTASEM O. TAHA, YUSUF AL-HIARI, YASSER BUSTANJI, HATIM S. ALKHATIB
Faculty of Pharmacy, University of Jordan, Queen Rania St., Amman 11942, Jordan
Received 20 March 2006; revised 28 June 2006; accepted 7 August 2006
Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.20764
ABSTRACT: Chitosan diacetate (CDA) was prepared by alkylating the amino moieties of
chitosan with mono-iodoacetic acid. Subsequently, CDA was cross-linked with Al3þ
,
Zn2þ, and Ca2þ ions to yield three ionotropically crosslinked polymeric matrices. These
composite matrices were characterized employing infrared spectroscopy (IR) and
differential scanning calorimetry (DSC). Subsequently, they were loaded with caffeine,
as a model drug, and were assessed as sustained release carriers by evaluating their
caffeine release profiles. Interestingly, only CDA-Zn2þ complex sustained the release of
caffeine effectively in a zero-order manner. The drug release and thermal behavior of the
tested matrices agree with the relative strength of the ionic or coordination character
of the bonds. This, in turn, depends on the position of the complexing ions on the
electrophilic softness/hardness scale. ß 2006 Wiley-Liss, Inc. and the American Pharmacists
Association J Pharm Sci 96:38–43, 2007
Keywords: controlled delivery; complexation; oral drug delivery; polymer synthesis;
polymeric drug delivery systems; chitosan diacetate; ionotropic crosslinking; Al3þ; Zn2þ
Ca2þ; electrophilic softness/hardness scale
;
INTRODUCTION
Polymer-metal composite materials have been
utilized in the development of sustained release
oral dosage forms.7–11
Accordingly, we report in this preliminary note
the synthesis of a new chitosan derivative, chit-
osan diacetate (CDA), and it is complexation to
aluminum, zinc and calcium ions. The new
composite materials were evaluated as potential
orally administered sustained-release carriers
using caffeine as a model drug.
Chitosan, obtained by alkaline deacetylation of
chitin,1 and its various semisynthetic derivatives,
have been attracting much attention due to its
natural origin, abundance, low cost, ready chemi-
cal modifiability and biocompatibility.2,3
Chitosan has been found to be an effective and
safe material in many drug delivery applications.4,5
The process of ionic crosslinking has attracted
much attention because of its simplicity, the
relatively mild preparation conditions,6 proce-
dural avoidance of possible toxicity of the reagents
commonly used for chemical cross-linking.6
METHODS
CDA was synthesized starting from chitosan and
iodoacetic acid, which was prepared in-situ from
sodium iodide and chloroacetic acid (Scheme 1).
The final polymer was purified by dialysis using a
Correspondence to: Khaled M. Aiedeh (Telephone: þ962-6-
535-5000 (Ext 2658); Fax: þ962-6-533-9649;
E-mail: Aiedeh@ju.edu.jo)
semi-permeable
membrane
(Membra-Cell,
Journal of Pharmaceutical Sciences, Vol. 96, 38–43 (2007)
MD44–14, MWCO 14,000, Viskase Companies,
ß 2006 Wiley-Liss, Inc. and the American Pharmacists Association
38
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 1, JANUARY 2007

RELEASE PROPERTIES OF CHITOSAN DIACETATE MATRICES
39
Scheme 1. Synthesis of CDA and subsequent crosslinking with metal ions.
Inc., Darien, IL) and characterized using infrared
spectroscopy and differential scanning calorime-
try. In addition, the isoelectric point of CDA was
estimated using potentiometric titration method.
CDA was crosslinked with ZnCl2, AlCl3, or
CaCl2 separately, and the resulting matrices were
loaded with caffeine. Subsequently, the different
polymeric composites were size-reduced and only
particles of the size range 125–250 mm were
collected and were characterized by infrared
spectroscopy (IR spectra were determined
between 500 and 4000 cmꢀ1 using the KBr disc
method in Nicolet Impact 400 IR spectrophot-
ometer, Nicolet Technologies, Waltham, MA) and
differential scanning calorimetry (DSC) (Thermo-
grams were recorded on Mettler-Toledo, Colum-
bus, OH, TA3000 System, samples were placed in
aluminum pans and heated at a rate of 108C/min
under nitrogen) (see Figs. 1 and 2).
Tablets with a nominal caffeine content of 100
mg were prepared by compressing the powdered
polymer-caffeine matrices at a compression force
of approximately 1500 Lb using a Korsch rotary
tablet press fitted with 9 mm convex punches. The
mixtures were compressed without addition of any
other excipient.
Caffeine release was tested in a USP Apparatus
#2 (Erweka DTD). The stirring rate and tempera-
ture were adjusted to 100 ꢁ 1 rpm and 37 ꢁ 0.58C
respectively. Nine hundred milliliters of 0.1 M HCl
was used as the dissolution medium for 2 h
afterwards it was replaced by 900 mL of phosphate
buffer of pH 6.8. At predetermined time intervals,
3 mL samples were withdrawn for analysis of
the released drug and replaced immediately
with fresh warmed medium. The drug content
was evaluated using UV spectrophotometry at
275 nm. The dissolution test was performed in
DOI 10.1002/jps
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 1, JANUARY 2007

40
AIEDEH ET AL.
triplicates and averages and standard deviations
were calculated.
RESULTS AND DISCUSSION
Synthesis and Characterization of CDA and CDA
Metal Complexes
CDA was prepared to simulate the structural
features of the metal chelating agent ethylene-
diamine tetraacetic acid (EDTA). Each glucosea-
mine monomeric block within chitosan was
targeted with two acetic acid groups, as shown
in Scheme 1. To enhance the efficiency of the
alkylation process, we employed mono-iodoacetic
acid as the alkylating agent due to the excellent
electrophilic properties of iodine. Mono-iodoacetic
acid was prepared in quantitative yield from the
corresponding chloro derivative via the Fickel-
stein Reaction,12 in which chlorine atom is
exchanged for iodine in acetone or acetonitrile.
The resulting polymer is characterized by good
solubility in acidic and basic media because of its
amphoteric properties (it contains amino moieties
in combination with carboxylic acid groups). The
reaction was ultimately terminated by precipita-
tion of the polymer in acetone.
The isoelectric point of the amphoteric CDA was
found to be within the range of 2–5. The IR profile
of CDA (Fig. 1) showed one major alteration upon
alkylation, a new sharp peak at around 1598 cmꢀ1
emerged corresponding to the newly introduced
carboxylate groups in CDA.
As expected, CDA precipitated fairly quickly
from its aqueous solutions upon exposure to
divalent and trivalent cations, which is probably
attributed to its chelating capacity, as proposed in
Scheme 1. The high molecular weights of resulting
complexes are expected to be the cause of their
quick precipitation. The complexation process can
be monitored and verified through infrared spec-
troscopy and DSC.
Figure 1 shows the infrared spectra of CDA
complexes with Al3þ, Ca2þ, and Zn2þ. Evidently
from the figure, the complexation of CDA to Al3þ
did not alter the position of the carboxylate band
significantly (ca. 1600 cmꢀ1), while on the other
hand, complexation to Ca2þ and Zn2þ caused
apparent shift to higher carbonyl stretching
vibrations (1629 and 1621 cmꢀ1, respectively).
Probably, this behavior is related to the electro-
philic softness and hardness of the metal cations.13
Aluminum ion is a hard electrophile capable of
Figure 1. Infrared spectra of chitosan, CDA, and
CDA-metal complexes.
forming significant electrostatic columbic bonds
with the carboxylate moieties of CDA,13 and
accordingly, it seems to allow significant negative
charges at the carboxylate moieties causing mini-
mal shifts in the position of the carboxylic stretch-
ing band. On the other hand, calcium and zinc ions
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 1, JANUARY 2007
DOI 10.1002/jps

RELEASE PROPERTIES OF CHITOSAN DIACETATE MATRICES
41
Figure 2. DSC thermograms of CDA and CDA-metal complexes.
are softer electrophiles13 capable of accepting
electrons from the carboxylate groups to form
covalent-like coordinate bonds, with the concomi-
tant loss of the negative charges of the carboxylate
moieties. This behavior seems to cause the
observed increase in the shift of the carboxylate
carbonyl stretching vibrations.14
Apparently, the coordinate bonds within Ca2þ
-
carboxylate complex resist breakdown within the
explored temperature range, causing the absence
of second endothermic bands in the CDA-Ca2þ
DSC trait. On the other hand, the presence of
aluminum ions in the CDA-Al3þ complex seems to
promote thermal degradation of the polymeric
complex at around 2158C leading to the observed
exothermic peak, which is probably due to the
strong acidic nature of Al3þ ions that promote
acidic degradation of the polysaccharide.
Figure 2 shows the DSC traits of uncomplexed
CDA and its complexes with Al3þ, Ca2þ, and Zn2þ
.
Evidently, the four materials exhibit endot-
hermic bands at 100–1108C corresponding to
the evaporation of hydration water molecules
attached to the polymeric backbone. Still, CDA-
Zn2þ complex illustrated shallower hydration
band, compared to the other complexes, probably
Release Profiles of Caffeine from the Different
CDA-Cationic Complexes
due to the reduced hydrophilicity of the Zn2þ
-
Figure 3 shows the release profiles of caffeine
from the three polymeric complexes compared to
the release profile from CDA alone. Evidently,
CDA-Al3þ was the quickest in releasing caffeine,
such that it is comparable to the release profile of
untreated CDA based matrices. Upon kinetic
analysis, CDA-Al3þ based matrices exhibited
carboxylate complex associated with the weaker
electrostatic properties of the Zn2þ-carboxylate
complex. Interestingly, CDA-Zn2þ complex illu-
strated a unique deep endothermic band at
around 1808C, which probably correspond to the
breakdown of Zn2þ-carboxylate coordination
complexes. This band is absent from the CDA-
Ca2þ complex, while the CDA-Al3þ complex
illustrated exothermic band at around 2158C.
a
zero order release rate of 13.14%/min
(R2 ¼ 0.8931) in comparison to 12.95%/min for
CDA based matrices (R2 ¼ 0.8748). On the other
DOI 10.1002/jps
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 1, JANUARY 2007

42
AIEDEH ET AL.
vehicles by evaluating their caffeine release
profiles. CDA-Zn2þ illustrated nearly zero-order
release profile. On the other hand, CDA-Al3þ
released loaded caffeine fairly quickly, while
CDA-Ca2þ illustrated an intermediate release
profile between those of CDA-Zn2þ and CDA-
Al3þ. These results seem to correlate with the
electrophilic hardness/softness of the metallic
cations, and should provide opportunity for fine-
tuning of drug release kinetics from such poly-
meric composites.
Figure 3. The release profile of caffeine from CDA
based tablets(ꢂ) and CDA cross-linked tablets with Al
(&), Ca (~) and Zn (^; Average of a triplicate ꢁ
standard deviation).
ACKNOWLEDGMENTS
The authors would like to acknowledge the
support of the Deanship of Scientific Research at
the University of Jordan (grant number 50/2003-
2004).
hand, CDA-Zn2þ sustained the release of caffeine
over 8 h via zero-order rate of 4.69%/min
(R2 ¼ 0.9244). However, CDA-Ca2þ illustrated an
intermediate behavior, that is, between CDA-Al3þ
and CDA-Zn2þ (release rate of 8.81 %/min and
R2 ¼ 0.9488). Once again, the most probable
explanation for this interesting behavior is based
on the electrophilic softness/hardness of the three
metallic cations. In the case of CDA-Al3þ, the
strong electrostatic nature of the Al3þ-carboxylate
complex renders the polymeric matrix hydrophilic
causing its relatively quick hydration and release
of the loaded model drug. However, in the case of
CDA-Zn2þ, the week electrostatic nature of the
coordination bonds within zinc-carboxylate com-
plexes render the polymeric complex less hydro-
philic. Furthermore, the crosslinking process
dramatically increases the molecular weight of
the polymeric complex, which further reduces its
water solubility and slows down its hydration and
drug-release rate. However, complexation to
calcium seems to render the corresponding poly-
meric complex of intermediate hydrophilic prop-
erties. This is consistent with the intermediate
position of calcium ions on the electrophilic soft-
ness/hardness scale.13
REFERENCES
1. Pourmorad F, Ebrahimzadeh MA, Honary S,
Ebrahimi P, Orangiyan M. 2005. Preparation of
chitin and chitosan from shrimp shell of Persian
Golf and the degree of deacetylation determination.
Int J Biol Biotechnol 2:429–432.
2. Berger J, Reist M, Mayer JM, Felt O, Gurny R.
2004. Structure and interactions in chitosan hydro-
gels formed by complexation or aggregation for
biomedical applications. Eur J Pharm Biopharm
57:35–52.
3. Prego C, Torres D, Alonso MJ. 2005. The potential
of chitosan for the oral administration of peptides.
Expert Opin Drug Deliv 2:843–854.
4. Varshosaz J, Sadrai H, Heidari A. 2006. Nasal
delivery of insulin using bioadhesive chitosan gels.
Drug Deliv 13:31–38.
5. Lu B, Xiong S-B, Yang H, Yin X-D, Zhao R-B. 2006.
Mitoxantrone-loaded BSA nanospheres and chito-
san nanospheres for local injection against breast
cancer and its lymph node metastases. Int J Pharm
307:175–181.
6. Prabaharan M, Mano J. 2005. Chitosan-based
particles as controlled drug delivery systems. Drug
Deliv 12:41–57.
CONCLUSIONS
7. Pongjanyakul T, Priprem A, Puttipipatkhachorn S.
2005. Investigation of novel alginate-magnesium
aluminum silicate microcomposite films for mod-
ified-release tablets. J Control Release 107:343–
356.
8. Taha MO, Aiedeh KM, Al-Hiari Y, Al-Khatib H.
2005. Synthesis of zinc-crosslinked thiolated algi-
nic acid beads and their in vitro evaluation as
potential enteric delivery system with folic acid as
model drug. Pharmazie 60:736–742.
CDA was successfully prepared by alkylating the
amino moieties of chitosan with mono-iodoacetic
acid. Subsequently, CDA was cross-linked with
Al3þ, Zn2þ, and Ca2þ to yield three ionotropically
crosslinked polymeric matrices. The composite
materials were characterized employing infrared
spectroscopy and DSC. Subsequently, the poly-
meric matrices were assessed as sustained release
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 1, JANUARY 2007
DOI 10.1002/jps

RELEASE PROPERTIES OF CHITOSAN DIACETATE MATRICES
43
9. AlKhatib HS, Taha MO, Aiedeh KM, Bustanji Y,
Sweileh B. Synthesis and in vitro behavior of iron-
crosslinked N-methyl and N-benzyl hydroxamated
derivatives of alginic acid as controlled release
carriers. Eur Polym J. In press.
10. Aiedeh K, Taha MO. 2001. Synthesis of iron-
crosslinked chitosan succinate and iron-crosslinked
hydroxamated chitosan succinate and their in vitro
evaluation as potential matrix materials for oral
theophylline sustained-release beads. Eur J Pharm
Sci 13:159–168.
phthalate as a matrix in prolonged-release, po-
tentially orally administered, chlorpheniramine
maleate granules. STP Pharma Sci 10:395–400.
12. Smith WB, Branum GD. 1981. The abnormal
Finkelstein reaction. A sequential ionic-free radical
reaction mechanism. Tetrahedron Lett 22:2055–
2058.
13. Fleming I. 1996. Frontier orbitals and organic
chemical reactions. First edition. London: John
Wiley and Sons Ltd. pp 1–32.
14. Wiliams DH, Fleming I. 1997. Spectroscopic meth-
ods in organic chemistry. 5th edition. London: The
McGraw-Hill Companies.
11. Taha MO, Aiedeh KM, Amro B. 2000. Investigation
of the suitability of chitosan-triethylene glycol
DOI 10.1002/jps
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 1, JANUARY 2007