Journal of Biomaterials

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Xanthan Gum as a Carrier for Controlled Release of Drugs

A. G. Andreopoulos and P. A. Tarantili
J Biomater Appl 2001 16: 34
DOI: 10.1106/XBFG-FYFX-9TW9-M83U

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 Xanthan Gum as a Carrier for
Controlled Release of Drugs

A. G. ANDREOPOULOS* AND P. A. TARANTILI

Department of Chemical Engineering, National Technical University of
Athens, 9 Iroon Polytechniou Str., 15780 Zografou, Athens, Greece

ABSTRACT: Systems based on xanthan gum matrix containing 1%, 2% and

5% salicylic acid were prepared and studied as controlled release devices.
Swelling of the matrix in distilled water and buffer solutions showed that
the ionic strength of the liquid has a strong effect on the sorptive properties of
the matrix. From the release experiments, conducted in distilled water at
37±0.5°C, it was found that the drug delivery process was accomplished within
the first 10 hours after immersion and salicylic acid was always released via a
non-Fickian transport. The phenomenon can be described by a release exponent
(n) in the area of 0.77 independently of the initial concentration of salicylic acid
in the xanthan matrix. These results can be interpreted taking into
consideration the dimensional and physical changes of the polymeric matrix
during swelling.

KEY WORDS: controlled release, biopolymers, xanthan gum, polymeric drug

carriers, swelling, salicylic acid.

INTRODUCTION

Ia plurality
t is well known that many polymeric materials are in use for the
design of controlled release devices, due to their versatility that allows
of properties to be combined. This class includes a great
variety of products, such as biodegradable materials, that decompose
into the human organism via hydrolytic or enzymic process (e.g.,
polyglycolic acid) as well as non-degradable polymers, that are stable

*Author to whom correspondence should be addressed.

34 JOURNAL OF BIOMATERIALS APPLICATIONS Volume 16 – July 2001

1530-8022/01/01 0034-13 $10.00/0 DOI: 10.1106/XBFG-FYFX-9TW9-M83U

© 2001 Technomic Publishing Co., Inc.
Journal Online at http://techpub.metapress.com

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 Xanthan Gum as a Carrier for Controlled Release of Drugs 35

for long periods upon exposure in the above conditions (e.g., acrylic
plastics) [1,2].
Natural polymers or modified biopolymers such as caraya gum or
modified cellulose are of interest for the above purpose together with
synthetic polymers such as acrylics. The aim in preparing sustained
delivery devices is to achieve “zero order release,” which guarantees a
constant rate of drug administration versus time [3]. This characteristic
appears adequate to produce a standard concentration into the human
body, adjusted to a level within the range of minimum effective and toxic
concentrations for a given drug [4].
According to the main mechanism of drug transport, controlled
release systems can be characterized as follows [5]:

• Matrix systems prepared by uniform dispersion of drug particles

throughout a solid non-erodible polymer [1]. The main processes for
drug release are diffusion through the polymer matrix or leaching by
the body fluids. At high drug concentrations a rather continuous
phase is formed among the particles and thus, pores and channels are
created facilitating further leaching.
• Bioerodible systems are polymers or blends susceptible to degradation
when in contact with living tissues [6–8]. As mentioned earlier, degra-
dation can be due to hydrolysis or enzymic scission of polymeric chains
and obviously, the decomposition products must be biocompatible. In
the case of bioerodible polymers release rate is controlled by the
kinetics of degradation of the polymeric system itself.
• Swelling control systems are prepared by dissolution or dispersion of a
drug into a polymer matrix. Normally, diffusion of the drug through
the polymer is restricted in these systems. However, biological fluids
can be absorbed by the polymeric matrix resulting in swelling, which is
accompanied by physical changes of the polymer. In the swollen state,
the transport of drug outside the matrix is accelerated. In this case, it
is evident that the rate of drug release is controlled by the degree of
swelling of the polymeric matrix.

Many synthetic polymers have already been studied as matrices for

sustained release of drugs, since their critical structural parameters can
be controlled during polymerization, which allows a tailor-made behav-
iour during drug delivery. However, natural polymers or preparations
based on biopolymers are still of great interest as they guarantee
biocompatibility and proper response with the human tissues.
A typical representative of this class of biomaterials is xanthan gum
(XG), the well-known high molecular weight extracellular polysac-

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36 A. G. ANDREOPOULOS AND P. A. TARANTILI

charide produced by bacteria of the genus Xanthomonas. Xanthan may

be chemically considered as an anionic polyelectrolyte, with a backbone
chain consisting of (1Æ4)β-D-glucan cellulose. The polymer backbone is
substituted at C-3 on alternate glucose residues with trisaccharide side
chain containing β-D-mannopyranosyl-(1→4)-(α-D-glucuropyranosyl)-
(1→2)-β-D-mannopyranoside 6-acetate. A pyruvic acid residue is linked
to 4 and 6 positions between 31–56% of the terminal D-mannose resi-
dues. In aqueous solutions, xanthan shows a conformational transition
from a random coil at elevated temperatures and low ionic strength to an
ordered double helix at physiologically relevant temperatures and salt
concentrations. Xanthan solutions show thickening properties with
pseudoplastic behaviour which is very stable over a wide range of
temperature and pH and in the presence of various types and amounts of
salts [9].
Talukdar and Kinget [10] studied the swelling and drug release behav-
iour of XG matrix. They concluded that swelling is strongly influenced
by the ionic strength and buffer concentrations, whereas release is
affected by the solubility of the drug and more specifically, an insoluble
drug follows a direct relationship with swelling of the polymer matrix
while a reciprocal relationship is observed with soluble drugs.
It was reported that XG showed interesting behaviour in the release of
diclofenac sodium when studied for the preparation of an oral sustained
release multiple-unit dosage form, in comparison with other hydrophilic
matrices like locust bean, carrageenan and karaya gum [11].
Due to the similarities in chemical structure between XG and
hydroxypropylmethyl cellulose (HPMC), some studies were carried out
for comparison of these two products with respect to their behaviour in
drug delivery. Some important pharmaceutical and economical advan-
tages of XG over HPMC are the absence of initial burst release, higher
drug-retarding ability, possibility of zero-order release kinetics and
better flowability. One disadvantage would be the influence of ionic
strength of the medium on drug release behaviour [12]. It was shown
that drug diffusion is faster in hydrated HPMC than in XG matrices.
Furthermore, diffusion of drug molecules in the hydrated gel of a XG
matrix tablet was found to be the main mechanism of overall release for
soluble drugs in contrast with insoluble drugs where other mechanisms
like matrix erosion control the phenomenon [13].
In this work, systems of XG with salicylic acid were prepared and
studied as controlled release devices. Selection of salicylic acid was based
on the fact that it shows intermediate solubility in distilled water and
therefore, the behaviour of such a system might be of interest. The
results for drug delivery measurements were discussed in combination

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 Xanthan Gum as a Carrier for Controlled Release of Drugs 37

with data derived from swelling experiments carried out with XG

tablets.

EXPERIMENTAL

Materials

The polymers used in this work were: finely powdered xanthan gum
(min. 92% less than 75 microns), kindly donated by Alteco Ltd. (Athens,
Greece). Salicylic acid (Fluka Chemie AG, Switzerland) was also used for
the incorporation to the polymeric matrix and preparation of the tablets.
Distilled water, and two buffer solutions consisting of citric acid and
di-sodium phosphate were used for immersion of the tablets prepared.
The v/v consistency of the buffer solutions was as follows: a) 48.5% of 0.1
F citric acid and 51.5% of 0.2 F di-sodium phosphate solutions, with pH
value 5 and b) 9.15% of 0.1 F citric acid and 90.85% of 0.2 F di-sodium
phosphate solutions, with pH value 7.5.

Method

Preparation of Tablets
Tablets were prepared using 500 mg of XG for each sample. The same
tablets were also prepared by using mixtures of XG containing 1%, 2%
and 5% salicylic acid as a model drug. The powders were hand filled and
compressed into a 9 mm die of a single punch tablet machine (Erweka AR
400) and compacted so that crashing strength was 8–9 kg without frac-
ture. This load was measured by employing the Erweka hardness tester.
The formulations used in this work are shown in Table 1.

Characterization of Tablets
The specimens prepared were characterized by measurements of both
the bulk and tapped density and the subsequent determination of

Table 1. Formulations of the prepared tablets.

Weight Salicylic Acid
Presentation Material (mg) (mg)
XG Xanthan gum 500 —
XG/SA Xanthan gum/Salicylic acid 495 5
XG/SA Xanthan gum/Salicylic acid 490 10
XG/SA Xanthan gum/Salicylic acid 475 25

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38 A. G. ANDREOPOULOS AND P. A. TARANTILI

Table 2. Characteristics of the polymer powder and tablets.

Bulk Density Tapped Density % Compressibility
Material (g/cm3 ±SD) (g/cm3 ±SD) ±SD
XG 0.450 ± 0.012 0.686 ± 0.040 52.44 ± 0.012

compressibility, as the percentage of the difference between the two

readings. Densities were measured according to methods reported in the
literature [14]. The results are shown in Table 2.

Swelling Measurements
Swelling was measured by immersing pre-weighed tablets into
beakers containing 300 ml of each one of the liquids under investigation,
i.e., distilled water and phosphate buffer solutions, pH: 5 and 7.5 at
25±0.5°C. Swelling in distilled water was also carried out at the temper-
ature of 37±0.5°C. At different time intervals, the tablets were removed,
wiped gently with a tissue to expel surface water and weighed.
Measurements were run in triplicate and the mean values and stan-
dard deviation were calculated.

Drug Release Experiments

XG tablets with 1%, 2% and 5% salicylic acid were immersed into
beakers containing 300 ml of distilled water and kept at 37±0.5°C. The
release was followed by uv- spectroscopy. Samples of 3 ml were taken at
various time intervals and their absorption intensity was measured in a
Hitachi U-1100 (Japan) uv-vis spectrophotometer at 296 nm.

RESULTS AND DISCUSSION

Swelling Index (SI)

The SI was calculated according to Equation (1)

 M − M0 
SI =  t  × 100 (1)
 M0 
where M0 is the initial weight of the tablet and Mt denotes the weight of
the tablet at time t.
The results obtained in various swelling media at room temperature
are shown in Figure 1, where essentially the same weight uptake can be
seen for specimens immersed in the buffer solutions, whereas distilled

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 Xanthan Gum as a Carrier for Controlled Release of Drugs 39

Figure 1. The swelling index in various liquids as a function of time, at 25°C.

water gives much higher swelling. The low sorption observed in the
phosphate solutions is independent of their pH values and can be attrib-
uted to the increased ionic strength of those liquids, which plays a crit-
ical role in the swelling capacity of XG as already reported. Similar
behaviour was recorded during the swelling of poly(methacrylic acid)
water. It was found that swelling is higher in de-ionized, as compared to
drinking water, which was attributed to interactions with the ions
present in the latter (15). Very interestingly, swelling of XG tablets
proceeds via the formation of a front due to water penetration, as shown
in Figure 2.
The effect of temperature on swelling of the xanthan tablets is
presented in Figure 3, in terms of the dependence of swelling index on
immersion time at the temperatures of 25 and 37°C. From the curves of
Figure 3 it is clear that higher ultimate swelling is achieved as the
temperature rises. However, the rate of sorption is comparable for both
temperatures, at least during the first stages of swelling.

Release of Salicylic Acid

The release of various loadings of salicylic acid (S.A.) in XG tablets at

37°C is shown in Figure 4, in terms of its concentration in distilled water.
From the curves of Figure 4, we can conclude that complete administra-

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40 A. G. ANDREOPOULOS AND P. A. TARANTILI

Figure 2. Photographs of xanthan tablets: (a) before immersion, (b) after 1 hour immer-
sion in water, at 37°C, (c) after 5 hours immersion in water at 37°C.

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 Xanthan Gum as a Carrier for Controlled Release of Drugs 41

Figure 3. Swelling of xanthan gum in distilled water, at 37°C.

Figure 4. The concentration of salicylic acid release from tablets as a function of time.

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42 A. G. ANDREOPOULOS AND P. A. TARANTILI

tion of S.A. takes place within about 10 hours after immersion,

independently of the initial concentration of each tablet. As expected,
the rate of delivery is considerably higher for S.A. concentration 5%.
The above data plotted in terms of Mt/M∞ versus time are presented in
Figure 5.
This treatment allows further analysis of the results obtained
according to the following exponential Equation (2).

Mt
= Kt n (2)
M∞

where Mt is the amount of S.A. released at time t, M∞ the total amount of

S.A. released and K is a constant incorporating structural and geometric
characteristics of the macromolecular polymeric system and the drug,
and n is a kinetic contact which depends on, and is used to characterize,
the transport mechanism.
The above equation is primarily useful for the analysis of data of
Fickian or non-Fickian diffusional release from non-swellable polymeric
delivery systems [16]. Many release processes from swellable polymers
fall between two limiting cases [17]:
1. Fickian release described by the relationship Mt/M∞ = 4(Dt/πl2)1/2,
where delivery is dependent on the square root of time

Figure 5. Release of salicylic acid from xanthan tablets, at 37°C.

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 Xanthan Gum as a Carrier for Controlled Release of Drugs 43

2. Case-II transport, controlled by the equation Mt/M∞ = C⋅t which

shows a linear dependence on time

Therefore, it seemed reasonable to approach these procedures by a

coupling of the Fickian and Case II transport mechanisms [18], which
leads again to the generalized expression of Equation (2).
For further analyzing our results, a fit of the release data in the above
equation was made for Mt/M∞ values up to 0.6. This fit is illustrated in
Figures 6–8 and the corresponding values of the constant K and the
exponent n for each case, are shown in Table 3.
From the data presented in Table 3 it is clear that non-Fickian release
takes place in all cases. Similar results were reported by Sujja-areevath
et al. [11], who studied the release of diclofenac sodium from XG
mini-matrix formulations. Interestingly, they reported a release expo-
nent (n) of 0.703 for XG. Also, for the systems XG/caffeine values of n
ranging from 0.68 to 0.78 were reported whereas for the XG/sodium
indomethacine systems the release exponent was determined in the area
of 0.73–0.84 [12]. It should be noted that those drugs are readily soluble
in water whereas salicylic acid shows a modest solubility.
On the other hand, the photographs of Figure 2 clearly show the
already mentioned swelling front, which is characteristic for glassy poly-
mers that often display Case II penetrant transport [19]. This means

Figure 6. The release process from xanthan tablet containing 1% salicylic acid.

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44 A. G. ANDREOPOULOS AND P. A. TARANTILI

Figure 7. The release process from xanthan tablet containing 2% salicylic acid.

Figure 8. The release process from xanthan tablet containing 5% salicylic acid.

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 Xanthan Gum as a Carrier for Controlled Release of Drugs 45

Table 3. Fit of release data in Equation (2).

S.A. Conc. (%) 1 2 5
K 0.0103 0.0099 0.0097
n 0.7756 0.7748 0.7711
Correlation coef., R2 0.9774 0.9969 0.9982

that the release exponent should be equal to 1, which is not consistent

with the experimental results of this work. For the interpretation of the
data obtained, the interrelation between diffusion and polymer chain
relaxation must be considered. In fact, when rate of diffusion is much
lower than that of relaxation then release depends on the square root of
time and obeys Fick’s law. In the case that relaxation process is very slow
compared with the rate of diffusion, which is usual for polymers in the
glassy state, then a linear dependence on time can be found. Finally,
when the order of magnitude of diffusion and relaxation rate are similar
then anomalous or non-Fickian transport is observed. It should be noted
that changes of the consistency and dimensional characteristics of the
swollen systems as well as possible erosion contribute to the complexity
of the phenomenon and should be further explored.

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