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Preparation and in vitro evaluation of mebeverine HCl colon-targeted drug

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DOI: 10.3109/10837451003739255 · Source: PubMed

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Pharmaceutical Development and Technology, 2011; 16(4): 331–342

RESEARCH ARTICLE

Preparation and in vitro evaluation of mebeverine HCl

colon-targeted drug delivery system
Ghassan Z. Abdullah, Muthanna F. Abdulkarim, Mallikarjun Chitneni, Ahmed F. Mutee,
Omar Z. Ameer, Ibrahim M. Salman, and Azmin M. Noor
School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia

Abstract
Mebeverine HCl is a water soluble drug commonly used to treat irritable bowel syndrome by acting directly
on the smooth muscles of the colon. This work was aimed at the formulation and in vitro evaluation of a
colon-targeted drug delivery system containing mebeverine HCl. Matrix tablets were prepared using ethyl
cellulose (EC), Eudragit RL 100 either solely or in combination by wet granulation technique. Dissolution was
carried out in 0.1 N HCl for 2 h followed by pH 6.8 phosphate buffer for eight hours. Uncoated forms released
more than 5% drug in 0.1 N HCl therefore, Eudragit L100 was used as a coat. The results indicated very slow
release profile. As a result, single retardant was used to prepare the matrix and coated by Eudragit L 100.
The matrix containing 7% Eudragit RL 100 and 6% of binder was subjected to further studies to assess the
effect of different coats (Eudragit L 100-55 and cellulose acetate phthalate) and different binders (pectin and
sodium alginate) on the release profile. Eudragit L 100 and pectin were the best coating agent and binder,
respectively. The final formula was stable and it can be concluded that the prepared system has the potential
to deliver mebeverine HCl in vivo to the colon.
Keywords:  Mebeverine Hcl; Eudragit; colon targeting; pectin

Introduction
The targeting of drugs to the colon as one of the oral
site-specific drug delivery systems had been thoroughly
studied and explored during the last decade. In general,
a colon-specific drug delivery system offers numerous
therapeutic advantages over the non-specific systems.
Many diseases that affect the colon, such as irritable
bowel syndrome (IBS), Crohn’s disease, colorectal cancer
and ulcerative colitis, can be treated more efficiently.[1]
The side-effects of drugs on healthy cells can be reduced
since the colon-specific drug delivery system increases
local availability, decreases systemic absorption and
minimizes the dose requirement.[2] Colon targeting is
also considered as one of the latest modified release
dosage forms that may enhance the systemic absorp-
tion of compounds hydrolyzed by the stomach acid or
metabolized by the pancreatic enzymes, e.g. proteins
and peptides.[3]
On the other hand, colon targeting system possesses
some negative drawbacks, such as the existence of differ-
ent types of bacteria and enzymes along the GI tract and
the variation in pH conditions and transit time from the
mouth to the colon.[4] In general, the in vitro dissolution
test that is used to assess the release characteristics of dif-
ferent oral site specific drug delivery systems is known to
be of tremendous importance. The dissolution tests envi-
ronment should closely mimic the in vivo circumstances
with regard to pH, fluid volume and the mixing intensity.
However, such conditions are very complex, if at all pos-
sible, to be standardized or validated. Nevertheless, vari-
ous dissolution methodologies and conditions had been
reported in the literature for the testing of colon-specific
drug delivery systems.[5,6] Since the colon is distally
located in the GI tract, a site specific dosage form should
restrain the release of drugs in the upper part of the GI
tract (stomach and small intestine) and should show an

Address for Correspondence:  Ghassan Z. Abdullah, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Minden, Penang, Malaysia.
Tel: +601 6409 2692. E-mail: ghassanalyasiri@yahoo.com

(Received 21 July 2009; revised 11 February 2010; accepted 11 February 2010)

ISSN 1083-7450 print/ISSN 1097-9867 online © 2011 Informa Healthcare USA, Inc.
DOI: 10.3109/10837451003739255 http://www.informahealthcare.com/phd
332   G. Z. Abdullah et al.
immediate onset of drug release upon entrance into the
colon.[7]
Thus, different techniques have been discovered and
reported by researchers for targeting drugs to the colon.
The oldest technique depended on enteric coating, e.g.
enteric-coated tablets, capsules or pellets. This was fol-
lowed by the pro-drug modification that had been used to
target different drugs, such as sulphasalazine. However,
the most common strategy is to load drugs in a system
that releases them in response to the stimuli of local
environment, like pH and enzymes. The use of biode-
gradable polymers to produce embedded drug swelling
matrix or coating the drug core with pH sensitive coat
has been considered by many researchers to be of great
interest.[8,9]
It is expected that such a system is able to preserve
drugs in the core of the formulation when they pass
through the upper GI tract and are released when they
enter the colon. Furthermore, this system still appears
to be one of the most attractive techniques from the
development and scale-up processes as well as from the
economic point of view.[10] In such systems, drug release
is preceded by the penetration of dissolution medium
into the porous matrix in order to dissolve the drug. This
is followed by the diffusion or leaching of the dissolved
molecules out of the matrix. Moreover, it has been shown
that the use of different combinations of various types of
polymers as matrix-forming materials enables appropri-
ate modification of the release characteristics of the drug
from the dosage form.[11,12] After all, such systems are still
susceptible to both internal and external individual vari-
ations such as health, physical and emotional situations,
diet, and whether in fed or fasted state that may alter the
pH of the GI tract.[4]
Recently, methacrylate resins have been widely used
to achieve these goals because of their variation in ionic
composition (polyelectrolyte), solubility, permeability
and swelling properties. Some of them are polycations
(Eudragit types E, RL, RS, and NE) and the others are
polyanions (Eudragit types L and S). Eudragit RL 100
is a copolymer which is synthesized from acrylic and
methacrylic acid esters. It is insoluble in water but
swells in digestive fluids autonomously of the pH and
becomes permeable. This polymer has many quater-
nary ammonium substitutions that convey positive
charges to its structure. It has been reported that it is to
be used mainly in tablets and granules film coating and
in matrix formulation.[9,13–15] Eudragit L 100 and L 100-55
are anionic in character due to the existence of carboxy-
late groups in their structure. Eudragit L 100 is based on
methacrylic acid and methyl methacrylate, insoluble in
water and artificial gastric fluid. It is soluble in neutral
to delicate alkaline region of the digestive tract and in
buffer solutions from pH 6 upwards. On the other hand,
Eudragit L 100-55, which is synthesized from methacrylic
acid and ethyl acrylate, is insoluble in artificial gastric
fluid and pure water. However, it may become soluble in
intestinal fluids and buffer solutions that demonstrate pH
5.5 upwards.[16–19]
Biodegradable polysaccharide polymers, like pec-
tin and sodium alginate, can satisfy to some extent the
requirements of colon-specific drug delivery. Sodium
alginate is a water soluble linear polymer derived from
brown seaweeds.[20] It is capable of forming membranes
for the separation as well as drug delivery applications.[21]
It shows a high gelling ability and viscosity in aqueous
solutions and demonstrates high aqueous stability as it is
not naturally degraded by mammal enzymes. Therefore,
sodium alginate is widely used in food, cosmetics and
pharmaceutical industries.[22] Pectin has the ability to
form three-dimensional networks through a non-cova-
lent cross linking (hydrogen-bonding, ionic association,
hydrophobic interaction, etc.) between the polymer
chains.[23] It demonstrates useful properties to remain
intact as an aggregate of macromolecules in acidic media,
while at neutral pH, its aggregates lean to dissociate and
swell. Pectin is also resistant to several enzymes, like pro-
teases and amylase which are active in the upper GI tract,
whereas it is digested by a large number of microfloras of
the colon and their enzymes. This degradation may be
overcome by using pectin in combination with Eudragit
RL, which leads to the formation of a complex combina-
tion as reported by Semdé et al. 2000.[24] Therefore, the
in vitro dissolution profiles may not be affected by the
presence of enzymes as pectin is not leached out from
the formed complex combination as compared to the in
vivo ones.[4,24]
Cellulose derivatives have engrossed significant inter-
est in pharmaceutical industry during the past decade.
Particularly, ethyl cellulose and cellulose acetate phtha-
late have gained considerable attention in many medici-
nal applications. Ethyl cellulose is susceptible to swelling,
non-toxic, stable and a hydrophobic polymer that has
been widely used in tablet coating, microencapsulation
and matrix tablets for both soluble and poorly soluble
drugs.[25,26] Cellulose acetate phthalate is a biodegradable
cellulose polymer commonly used as an enteric coating
material or matrix binder for tablets and capsules at such
concentrations of 0.5–9%. Cellulose acetate phthalate
film coating reveals an extended resistance to dissolution
in strongly acidic gastric fluid, but it dissolves in mildly
acidic or neutral intestinal environment.[27] The versatility
of the composition of these polymers make them appli-
cable and feasible for the preparation of enteric drug for-
mulation or matrix dosage forms that control the release
of drugs through polymer swelling and pH-dependent
solubility.[17,28,29]
Mebeverine HCl is a white crystalline powder freely
soluble in water and ethanol and practically insoluble in
diethyl ether. It has a pka of approximately 10 and short
 Mebeverine HCl colon-targeted tablets   333

plasma half-life of 2.5 h with frequent ­administration rate
due to its short half-life.[30] Mebeverine HCl (Duspatalin
Retard, Solvay Pharmaceutics) is available as 200 mg
extended release capsule in the market and the recom-
mended dose is twice daily.[31] It is used for its musculo-
tropic antispasmodic activity that directly acts on the
smooth muscles of the gastrointestinal (GI) tract. It is
efficiently used in the treatment of IBS a disorder char-
acterized by abdominal pain and disordered defecation.
Mebeverine HCl does not affect normal gut motility since
its action does not include the activation of autonomic
nervous system.[32–34]
The aim of the current work was to prepare a modi-
fied release colon targeted tablet dosage form containing
mebeverine HCl. Different types and concentrations of
retardants and colon drug targeting polymers were used
as matrix forming agents (Eudragit RL 100 and ethyl cel-
lulose) and coatings (Eudragit L 100, Eudragit L 100-55
and cellulose acetate phthalate). In addition, different
types of binders (pectin and sodium alginate) were uti-
lized to study their effects on the release profiles of the
drug from the prepared formulae.
Materials and methods
Materials
Mebeverine HCl was purchased from Sigma-Aldrich
Chemie, GmbH, Germany. Eudragit RL100 (Eud RL
100) was purchased from Röhm Pharma, GmbH,
Germany, Ethyl cellulose (EC) was purchased from
BDH Chemicals Ltd, Liverpool, UK. Sodium alginate and
pectin HM were supplied by Sigma-Aldrich (USA) and
Fluka (Switzerland), respectively. In addition, lactose
and chloroform were purchased from BDH Chemicals
Ltd, Liverpool, and were used for the preparation of
the pellet matrix tablets. Eudragit L100 (Eud L 100)
and Eudragit L 100-55 (Eud L 100-55) were provided by
Röhm Pharma, GmbH, Germany while cellulose acetate
phthalate (CAP) was purchased from BDH Chemicals
Ltd, Liverpool, UK. Other solvents including ethanol,
acetone, isopropanol, dibutyl phthalate, propylene gly-
col and sorbitan mono-oleate were purchased from BDH
Chemicals Ltd, Liverpool, UK, and were used to prepare
the coating solutions for colon-targeting purposes. The
other chemicals used as formulation additives include
hydrochloric acid, orthophosphoric acid, dihydrogen
potassium ortho-phosphate were purchased from BDH
Chemicals Ltd, Liverpool, UK, while magnesium stearate
was purchased from Barbeher, GmbH, Germany. Sodium
hydroxide was purchased from Merck, Germany. Finally,
pectinex 3XL (3000 FDU/mL) was obtained from Novo-
Nordisk Ferment Ltd, Switzerland. All other reagents
were of analytical grade.
Methods
Preparation of enteric-coated colon targeted matrix
tablets
This work involved the preparation of different modified
release dosage forms of mebeverine HCl by embedding
the drug in different matrix components to ensure its
slow release and to target it to the colon through either
the use of certain ingredients in the matrix or by using
different types of coating materials.
(a) Preparation of enteric-coated tablets containing a
mixture of retarding polymers.  The composition of the
core tablets is shown in Table 1 (formulae 1–6). A wet
granulation method was used to prepare the granules of
the tablets. The grounded powder of mebeverine HCl,
EC, pectin and lactose were blended together for 5 min,
followed by the drop-by-drop addition of the granulat-
ing solution of the second retarding polymer, which was
prepared by dissolving the desired amount of Eud RL 100
in chloroform until the end point was reached by using
the ball test (the ball test is a rough way of determining
the end point). It was conducted by pressing a portion of
the wet mass in the palm of the hand to form a ball like
mass, followed by the application of a moderate pressure
to crumble the ball.[11]
The wet mass was then forced through a 12-mesh size
screen and dried in an oven at 50°C for 2 h. The dried
granules were then molded into sizes by passing them
through an 18-mesh size screen. Finally, magnesium
stearate was added and mixed with the granules for two
minutes. The tablet formation was accomplished by using
a rotary double punch tablet machine ( Korsch, EKO type,
Erweka, GmbH. Offenbach, Germany). Concave punches

Table 1.  Composition of mebeverine HCl formulae prepared as a modified release tablet dosage form.
Contents (%) F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 F13 F14 F15 F16
Mebeverine HCl 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50
Eudragit® RL100 15 15 15 20 25 30 5 10 15 - - - 7 8 9 7
Ethyl cellulose 5 7.5 10 10 10 10 - - - 5 10 15 - - - -
Pectin 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6
Sodium alginate - - - - - - - - - - - - - - - 6
Lactose 23 20.5 18 13 8 3 38 33 28 38 33 28 36 35 34 36
Mg stearate 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1
Total weight 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100
334   G. Z. Abdullah et al.
of 8 mm in diameter were used for the preparation of the
core tablets. The thickness of the tablets was 5.2 mm. The
produced tablets were then divided into two groups;
one for studying the effect of retarding polymers on the
physical properties of uncoated tablets while the other
half was for the production of coated tablets. The residual
chloroform content in the dried granules was measured
using gas chromatography and was found to be 10 ppm,
which is well within the acceptable limits specified by
ICH harmonised tripartite guidelines.
(b) Preparation of enteric-coated tablets containing ­single
retarding polymer.  The core tablets composition is
shown in Table 1 (formulae 7–12). Formulae 7–9 were
prepared by blending the milled ingredients (mebeverine
HCl, pectin and lactose) together for 5 min, followed by
the addition of the granulating solution of the retarding
polymer, which was Eud RL 100, drop-by-drop until the
end point was reached. The remaining steps of drying,
sieving, compression and coating were completed as for
formula (1–6) to produce the final tablets.
Formulae 9–12 tablets were prepared by using the
same procedure as for formulae 7–9 but by using dif-
ferent granulating solution (EC in ethanol 99%), which
was prepared by dissolving the desired amount of EC in
a sufficient volume of ethanol. The rest of the steps were
as aforementioned.
(c) Optimization of the amount of the selected matrix
retardant.  Formulae 13–15, illustrated in Table 1, were
prepared to optimize the final amount of Eud RL 100,
the selected matrix retardant, for further investigation.
The same method for preparing the tablets was used.
The concentration of all excipients and drug were kept
constant, except for the filler and Eud RL 100.
(d) Preparation of enteric-coated tablet containing
two different types of binder and Eud RL 100 as matrix
­retardant.  The composition of the core tablets is given
in Table 1 (formulae 13 and 16). These formulae were
prepared through the same procedure as for formulae
7–9 except that, in formula 16, another binder (sodium
alginate) was used instead of pectin which was used in
formula 13. The concentration of the binders used was
the same in order to study the effect of changing the type
of binder on the release of the drug from the matrix sys-
tem that contains Eud RL 100 as a retardant.
Preparation of coating and granulating solutions
(a) Preparation of Eud L 100 and L 100-55 coating
­solutions.  The coating solutions of these pH-sensitive
polymers were prepared by weighing 3.48 g of Eud L 100
or Eud L 100-55 and mixed with 65.6 mL and 16.7 mL of
isopropanol and acetone, respectively, for 2 min. This was
then followed by the addition of 0.68 mL dibutyl phthalate
as plasticizer and 0.01 mL of semithicone as anti-foaming
agent. The whole mixture was sonicated for about 10 min
to ensure complete dissolution of the polymers and the
formation of a clear coating solution.
(b) Preparation of CAP coating solution.  This solution
was prepared by mixing 4 g of CAP with 3 mL of propylene
glycol and 1 mL of the solubilizing agent sorbitan mono-
oleate (Span® 20). The mixture was shaken in a solvent
system (ethanol 45 mL and acetone as required to pro-
duce 100 mL) in a well-closed container until the desired
clear solution was obtained.[11]
(c) Preparation of granulating solution.  The granulating
solution was prepared by mixing the desired amount of
Eud RL 100 with some milliliters of chloroform accord-
ing to its solubility which is equal to 15 g/100 g.[13] The
mixture was heated in a water bath at 30°C and stirred
continuously for 20 min so as to obtain a homogenous
­transparent solution.
Enteric coating
The coating of the matrix colon targeted tablets was car-
ried out by using a coating machine under the following
conditions: 2.5 kg/cm2 of spray air pressure; 10 mL/min
of spray solution feed; between 30 and 40°C temperature;
and the rotating speed of pan 8.5 rpm (Kothra Pharma,
Mumbai, India). The coated tablets were dried for 10 h
at 45°C. The weight of the coating layer was about 8 mg
per tablet.
Assay for the total amount of mebeverine HCl in the
­modified release tablets
Twenty tablets of each prepared formula were weighed
and transformed into powder form. A quantity of the
powdered tablet which is equivalent to 0.5 g of mebever-
ine HCl was mixed with 100 mL of 0.1 M HCl and heated
for 10 min in a water bath 40°C with occasional shaking.
The resultant mixture was cooled and a sufficient amount
of 0.1 M HCl was added to produce 250 mL solution which
was then filtered. A sufficient amount of 0.1 M HCl was
added to 10 mL of the filtrate in order to produce 100 mL;
15 mL of the resulting solution was then diluted to 100 mL
with the same solvent. The absorbance of this solution
was measured at a maximum wave length (λ max) of
263 nm. The content of mebeverine HCl was calculated
by taking the maximum value at 263 as the value of A
(1%, 1 cm).[35]
Physical properties and evaluation measurements for
the prepared tablets
Hardness test.  This test was conducted on 20 uncoated
tablets of all prepared formulae which were randomly
picked. The YD-2 tablet hardness tester (Vanguard
Pharmaceutical Machinery Inc. China) was used to
determine the hardness of each tablet.
Friability test.  The friability test on 20 randomly
selected uncoated tablets from each prepared formula

was carried out in order to ensure that the tablets were
compact enough for coating. The CS-1 tablet friability
tester (Vanguard Pharmaceutical Machinery Inc. China)
was used at a speed of 25 rpm for 4 min.
Weight variation test before coating.  This test was
performed to guarantee that the drug was distributed
uniformly throughout the prepared tablets; 20 uncoated
tablets from each formula were picked randomly. The
weight of each tablet was recorded and the weight
­variation was calculated.
Weight variation test after coating.  This test was carried
out on 20 randomly selected coated tablets of each for-
mula. The weight of each coated tablet before coating was
measured and the weight variations as a result of coating
were determined.
In vitro dissolution tests.  In drug release studies of
uncoated and coated core tablet formulations, the chang-
ing pH media (Method 1, USP 27) for delayed release
tablets was used. The dissolution test was conducted in
USP rotating paddle apparatus (Distek Premiere 5100,
auto-sampler dissolution test system, USA) with a stirring
rate of 100 rpm at 37 ± 0.5°C.[36] The initial drug release
was carried out in 0.1 N HCl (pH 1.2) for 2 h followed
by phosphate buffer pH 6.8 for 8 h at 37 ± 0.5°C.[37] The
filtered aliquots of dissolution media were withdrawn at
regular intervals and immediately replaced by the same
volume of fresh media. These samples were analyzed for
the amount of mebeverine HCl released spectrophoto-
metrically at 263 nm. Dissolution tests were performed at
least six times for each sample. In addition to this study,
the dissolution study was also performed on the opti-
mized formulation with the addition of pectinase (3 mL
of pectinex) to the dissolution medium after the first 2-h
run in 0.1 N HCl.
Further study on selected modified release formula
Formula 13 was selected for further studies to evaluate
the effect of coating material on the dissolution profile of
the drug and the stability evaluation, including the effect
of elevated temperature and the effect of light.
Effect of types of coating.  Formula 13 was coated with
two different coating solutions, Eud L 100-55 and CAP, in
order to study the effects of these coating materials on the
release of drug from Eud RL 100 matrix tablets.
Stability study
Effect of temperature.  The effect of temperature on
the degradation rate of mebeverine HCl in the selected
modified release dosage form (formula 13) was studied.
A specific number of tablets were stored at three differ-
ent temperatures (40, 50 and 60°C) for six months. At
some specified time intervals, the physical stability of the
­tablets was checked by conducting the assay.
Effect of light (photosensitivity).  A study was made on the
influence of light on the degradation rate of mebeverine
Mebeverine HCl colon-targeted tablets   335
HCl in formula 13 of both coated tablets (with Eud L
100), as well as uncoated ones. These two tablet forms
were left exposed to tungsten light for six months and
then analyzed for the amount of active ingredients that
remained after exposure. The drug dissolution profile was
also checked over the same period.
Statistical analysis
The statistical analysis of all the collected data was proc-
essed using SPSS version 16. One-way ANOVA test was
used to measure the significant differences between the
prepared formulae. Statistically, the significant difference
was considered to be at (P < 0.05).
Results and discussion
Physical properties and evaluation measurements for
the prepared tablets
Several evaluation tests, as described previously, were
carried out on the 16 prepared formulae.
Hardness test
The mean hardness for all prepared formulations was
between 12–14.5 kg. There was no specific hardness value
being mentioned. However, a higher value of more than 8
is most preferred as it could contribute to a longer period
of drug release.[11]
Friability test
The percentage of weight loss of all the formulae being
tested was less than 1% which matches the acceptable
range.[11,35]
Weight variation test before coating
The weight variation for all formulations tested was
within the acceptable limit of less than 5%.[35]
Weight variation after coating
The weight variation test for coated tablets was conducted
in order to ensure the uniformity of the coating layer. The
results of this test showed that the weight of all the 20
tablets of all formulae had increased by 8 ± 0.5 mg mean-
ing that there was less than 10% w/w increase or decrease
in the percentage of coating which fulfilled the general
requirements of coating.[11]
In vitro dissolution tests
Effect of EC on Eud RL 100 percentage ratio on uncoated
tablets.  These dissolution tests were conducted in order
to study the effect of changing the percentage of EC and
Eud RL 100, as combined polymers, in controlling the
release of the drug from the resultant tablets. The results
336   G. Z. Abdullah et al.

shown in Figures 1 and 2 demonstrate an insignificant
decrease (P > 0.05) in the drug release from the tablets
as the percentage ratio of ethyl cellulose (EC) on Eud RL
100 changes (i.e. an increase of EC concentration with
a constant Eud RL 100 concentration and vice-versa)
with a well recognized problem of high percentage of
drug release during the first 2 h of the test using the arti-
ficial gastric fluid (pH 1.2).[11] This is also called the burst
effect.
These results could be due to the fact that the drug is
freely soluble in water and the mechanism of action of EC
and Eud RL 100 as retardants depends on the absorption
of water until the time when hydration is complete. Double
burst effect was observed in Figure 1 in which the first one
120
100
80
Drug release (%)
may be due to the time taken by the polymers to swell and
the second burst may be due to the complete erosion of
EC and the existence of only one polymer out of the two
initially present. Additionally, the concentration of Eud RL
100 in formulae 1–3 was lower than in formulae 4–6.
The solely burst effect shown in Figure 2 may be due to
the ratio of Eud RL 100 to EC. Furthermore, EC may have
a tendency to mask the quaternary ammonium groups
present in Eud RL 100 to some extent, thereby modify-
ing the release of the drug. Although, Eud RL 100 and EC
were present in formulae 1–6, there was a difference in
the release pattern due to the difference in the ratio of
pH-independent retardants (Eud RL 100 to EC).[38]
Equation 1 (Krosmeyer-Peppas equation) was used to
describe the drug release mechanism by calculating the
diffusion exponent or n value as listed in Table 2.[39] In the
case of bimodal dissolution profiles (Figure 1), Peppas
equation was not calculated because the accuracy of cal-
culation of diffusion exponent parameter would suffer in
later stages as we expect one polymer (EC) to get eroded

away completely in the process. In case of dissolution

profiles with lag time, the lag time was excluded before
60 performing the calculation.[40]
The n value obtained from formulae 4–6 indicates that
40 the drug release is controlled by the Fickian diffusion
(F1) Eud. RL 100 (15%) - EC (5%) process since the calculated n value is less than 0.5.[41]
20 (F2) Eud. RL 100 (15%) - EC (7.5%)
These results indicated that a certain period of time is
required for EC and Eud RL 100 to exert their effects.
(F3) Eud. RL 100 (15%) - EC (10%)
0
0 60 120 180 240 300 360 420 480 540 600 660 Mt
F= = Kt n (1)
Time (min) M0

Figure 1.  Effect of ethyl cellulose concentrations added to Eudragit® where: F is the fractional release of drug, Mt is the amount
RL 100 matrices on the release profile of mebeverine HCl from
uncoated tablets. (Mean ± SD, n = 6).
of drug released at time t, M0 is the initial amount of drug,

120 Table 2.  Calculated diffusion exponent (n) and R2 using Krosmeyer-
Peppas equation.
n value R2 n value R2
100
Formula no. Uncoated Uncoated Coated Coated
F1 - - 0.8924 0.966
80
Drug release (%)

F2 - - 0.8741 0.971
F3 - - 0.8345 0.980
60 F4 0.3752 0.992 0.8891 0.910
F5 0.3519 0.988 0.8756 0.980
40 F6 0.3223 0.963 0.8686 0.963
F7 - - 1.0615 0.996
(F4) Eud. RL 100 (20%) - EC (10%)
F8 - - 0.9891 0.990
20 (F5) Eud. RL 100 (25%) - EC (10%) F9 - - 0.8653 0.959
(F6) Eud. RL 100 (30%) - EC (10%) F10 - - 0.9356 0.961
0 F11 - - 0.7994 0.989
0 60 120 180 240 300 360 420 480 540 600 660 F12 - - 0.6421 0.930
Time (min) F13 - - 0.9864 0.994
F14 - - 0.9670 0.995
Figure 2.  Effect of Eudragit® RL 100 concentrations added to ethyl
F15 - - 0.9560 0.991
cellulose matrices on the release profile of mebeverine HCl from
uncoated tablets. (Mean ± SD, n = 6). F16 - - 1.0030 0.983

K is the release rate constant, n is a constant known as the
diffusion exponent.
By referring to the percentage of drug released after
10 h, it is obvious that an increase of the concentration of
Eud RL 100 with a constant EC concentration would pro-
duce a significant decrease (P < 0.05) in the drug release
from the matrix system as compared to those achieved by
increasing the concentration of EC with the concentra-
tion of Eud RL 100 kept constant.
Effects of EC to Eud. RL 100 percentage ratio on coated
tablets.  In this study, the tablets produced as accord-
ing to formulae 1–6 were coated with Eud L 100 solution.
Figures  3 and 4 demonstrate an insignificant decrease
(P > 0.05) in the drug release from the two polymers
matrix system as the ratio between the retarding ­polymers
changes.
The release mechanism was determined by using
Equation 1. The n values (Table 2) of the coated formu-
lae 1–6 tablets were higher than 0.5 which shows that an
anomalous non-Fickian diffusion process is the mecha-
nism of drug release which is totally different from that
for the uncoated tablets. This mechanism can explain
the results presented in Figures 3 and 4, which show
that there is a high reduction in the percentage of drug
released over the first 2 h as a result of the protecting
effect provided by the coating layer with a greater control
to the overall release profile of coated tablets in compari-
son with uncoated ones.[16]
This might be attributed to the fact that Eud L 100
is pH-dependent anionic polymer which is soluble
at pH above 6.0 and needs a certain period of time to
dissolve in the intestinal fluid. This provides enough
time for the matrix retardants to swell completely and
exert their maximum retarding mechanism. The dis-
solution of hydrophilic polymer (Eud RL 100) occurs
120
(F1) Eud. RL 100 (15%) - EC (5%)
(F2) Eud. RL 100 (15%) - EC (7.5%)
100
(F3) Eud. RL 100 (15%) - EC (10%)
80
Drug release (%)
60
40
20
0 0
0 60 120 180 240 300 360 420 480 540 600 660
Time (min)
Figure 3.  Effect of ethyl cellulose concentrations added to Eudragit®
RL 100 matrices on the release profile of mebeverine HCl from coated
tablets. (Mean ± SD, n = 6).
Mebeverine HCl colon-targeted tablets   337
via two distinctive processes, swelling and subsequent
­erosion (i.e. chain disentanglement) at the dissolution
front, which include the transition from glassy to rub-
bery phase as a result of water ingress leading to the
formation of the polymer gel. Water ingress contin-
ues till these swollen chains reach a disentanglement
threshold value at the periphery of gel layer. Therefore,
drug release from swellable polymeric system in the
late-time period is predominantly governed by polymer
relaxation and erosion.[38,42,43] EC has a natural tendency
to erode in water due to separation of the surface parti-
cles of the matrix. Erosion occurs slowly and this might
be the ­probable mechanism of drug release from the
matrix.[44]
Effects of matrix Eud RL 100 concentration of coated
­tablets.  Due to the excessive release control provided
by the combined matrix retardant and the coating layer,
a single retardant polymer formulation was prepared in
order to study the effect of each polymer formulation as
well as to achieve the desired controlling efficiency.
Formulae 7, 8 and 9 containing Eud RL 100 as matrix
forming agent (5, 10 and 15% w/w), were prepared and
coated with Eud L 100 solution of the same concentra-
tion aforementioned. The data presented in Figure 5
shows that there is a significant decrease (P < 0.05) in
the release of drug from the matrix coated tablets as the
matrix forming agent concentration increases. Also, it
can be seen that the amount of drug liberated from the
tablets in the gastric fluid is well controlled and does
not exceed the recommended percentage of release for
an enteric coated controlled release tablet which is not
more than 5%.[35] This might be attributed to the protec-
tive effect of the coating and the anomalous non Fickian
diffusion mechanism presented by these three formu-
lae (n > 0.5). Furthermore, this coating layer protected
120
(F4) Eud. RL 100 (20%) - EC (5%)
(F5) Eud. RL 100 (25%) - EC (7.5%)
100
(F6) Eud. RL 100 (30%) - EC (10%)
80
Drug release (%)
60
40
20
0 60 120 180 240 300 360 420 480 540 600 660
Time (min)
Figure 4.  Effect of Eudragit® RL 100 concentrations added to ethyl cel-
lulose matrices on the release profile of mebeverine HCl from coated
tablets. (Mean ± SD, n = 6).
338   G. Z. Abdullah et al.

pectin from being extensively dissolved in the gastric
media. As a result, Eud RL 100 (together with pectin)
formed the gel structure which synergizes each other
in controlling the drug release after the dissolution of
coating.[45,46]
Effects of matrix EC concentration of coated tablets.
Formulae 10, 11 and 12 containing EC as matrix form-
ing agent (5, 10 and 15% w/w) were prepared and
coated with Eud L 100 solution of the same concentra-
tion as previously mentioned. The analysis of the data
presented in Figure 6 shows a significant decrease
(P < 0.05) in the release of drug as the concentration of EC
increases. This is due to anomalous non-Fickian diffusion
­mechanism (n > 0.5), the coating defensive effect, and the
120
100
80
Drug release (%)
susceptibility to swelling and gel formation of pectin as
in the case of formulae 7, 8 and 9.[44]
By comparing the percentage of the drug released
after 10 h [formula 7 vs. 10, formula 8 vs. 11 and for-
mula 9 vs. 12], a significant difference (P < 0.05) was
observed (P < 0.05). Therefore, Eud RL 100 shows a potent
­controlling efficiency as a matrix retardant as compared
to EC.
Optimization of the amount of Eud RL 100 as a single
matrix retardant.  Formulae 13–15 containing 7, 8
and 9% of Eud RL 100, respectively, were prepared and
their release profile was compared with that of formula
8 in order to optimize the final amount of Eud RL as
a single matrix retardant. Figure 7 illustrates an insig-
nificant change (P > 0.05) in the whole release profile
and the total amount of drug released. The n  values
(Table 2) were higher than 0.5 which indicate the same
non-­Fickian diffusion mechanism with the same diffu-
sive characteristics aforementioned. Formula 13 which
contains 7% of Eud RL 100 was selected for further

studies as there was an insignificant difference in the

release profiles of the formulae containing 7–10% of this
60
polymer.
Types of binder.  Basically, the 7% of Eud RL 100 used in
40 the matrix together with 8 mg of Eud L 100 used as coating
proved to be successful in accomplishing the goals of the
20 (F7) Eud. RL 100 (5%) drug release modification. However, further investigation
(F8) Eud. RL 100 (10%) was conducted by changing the type of binder used to
0 (F9) Eud. RL 100 (15%) evaluate the effect of different binding properties on the
0 60 120 180 240 300 360 420 480 540 600 660 final release profile of the drug. Formula 16, presented
Time (min) in Table 1, was prepared by using sodium alginate as a
binder, instead of pectin, at the same concentration level.
Figure 5.  Effect of change in the matrix Eudragit® RL 100 concentra-
The dissolution profile of this formula was compared to
tions on the release profile of mebeverine HCl of coated tablets. (Mean
± SD, n = 6). that of formula 13, as shown in Figure 8, which obviously
shows a significant difference (P < 0.05) in the release
120
120

100
100

80
80
Drug release (%)

Drug release (%)

60
60

40
40

20 (F10) EC (5%) (F13) Eud. RL 100 (7%)

(F11) EC (10%) 20 (F14) Eud. RL 100 (8%)
(F12) EC (15%) (F15) Eud. RL 100 (9%)
0 (F8) Eud. RL 100 (10 %)
0 60 120 180 240 300 360 420 480 540 600 660 0
Time (min) 0 60 120 180 240 300 360 420 480 540 600 660
Time (min)
Figure 6.  Effect of change in the matrix ethyl cellulose concentrations
on the release profile of mebeverine HCl of coated tablets. (Mean ± Figure 7.  Optimization of the matrix Eudragit® RL 100 concentrations.
SD, n = 6). (Mean ± SD, n = 6).
 Mebeverine HCl colon-targeted tablets   339

profile of drug. Formula 16, which contained sodium
alginate, released more than 10% of drug in 0.1 N HCl
over the first 2 h.
Furthermore, the dissolution curve of formula 16 was
erratic and did not liberate 100% of mebeverine HCl
over 10 h which should be released to achieve a better
response. Both sodium alginate and pectin formed a
three-dimensional gel network responsible for the retar-
dation of drug release. However, as reported previously by
Pornsak et al. (2007),[47] sodium alginate was discovered
to be more sensitive to gastric media and initially could
not form a strong release retarding layer in combination
with Eud RL 100. Thus, formula 13 was a better choice as
a good candidate to release the drug in a regular modified
manner and was subjected to further studies in order to
assess its stability.
to a higher drug diffusion and solubility in the intestinal
fluid.[16,27]
Effect of pectinase enzyme on the dissolution profile of
the optimized formulation
The dissolution profile of formulation F13 in the presence
and absence of pectinase enzyme is shown in Figure 10.
From the result obtained it was obvious that even though
the release in presence of the enzyme was little faster, it
was not significantly different from that without pecti-
nase. The probable reason may be that pectin HM inter-
acts with Eud RL 100 to form a complex. The pectin is not
in the free form so the enzyme activity on pectin is not
that predominant. The results obtained were in a good
correlation to that obtained by Semdé et al.[24]

Effect of coating types 120

In this study, two different types of enteric coating poly-

100
mers were used for formula 13. The same concentration
and coating percentage of Eud L 100 was used to study
the effect of coating polymer on the release profile of the 80
Drug release (%)

drug. This led to the discovery that the calculated n value

had demonstrated an anomalous non-Fickian diffusion 60
mechanism (n > 0.5) regardless of the type of coating
polymer being used. 40
Comparatively, the first 2 h of release in 0.1 N HCl
(Figure 9) revealed a significant difference (P < 0.05) in Coat-CAP
20
the release profile amongst the three formulae, thereby Coat-Eud. L 100-55

indicating a higher retarding efficiency of Eud L 100 in Coat-Eud. L 100

the gastric fluid as compared to Eud L 100-55 and CAP.
Similar results were obtained in the intestinal fluid pH 6.8
for the first 4 h of dissolution study. This could be due to
the faster dissolution of Eud L 100-55 and CAP coats than
Eud L 100 coat in the intestinal fluid (pH 6.8) which leads
0
0 60 120 180 240 300 360 420 480 540 600 660
Time (min)
Figure 9.  Effect of type of coating polymer on the release profile of
mebeverine HCl of coated tablets. (Mean ± SD, n = 6).

120 120
(F13) without pectinase enzyme
(F13) with pectinase enzyme
100 100

80 80
Drug release (%)
Drug release (%)

60 60

40 40

20 20
(F13) Pectin (6%)
(F16) Sodium alginate (6%)
0 0
0 60 120 180 240 300 360 420 480 540 600 660 0 60 120 180 240 300 360 420 480 540 600 660
Time (min) Time (min)

Figure 8.  Effect of type of binder on the release profile of mebeverine Figure 10.  Effect of pectinase enzyme on the release profile of
HCl of coated tablets. (Mean ± SD, n = 6). ­optimized formulation (F13). (Mean ± SD, n = 6).
340   G. Z. Abdullah et al.
Stability study
Effect of temperature
The stability study on the selected formula 13 at three
different temperatures (40, 50, and 60°C) for six months
showed that there were minor changes in the total con-
tents of mebeverine HCl within the tablets at all the tem-
peratures observed. The degradation of mebeverine HCl
followed first order kinetics.[42]
The degradation rate constant (K) at each temperature,
as shown in Table 3, was calculated by using the slope of
each line. The expiration date (t 10%) was then measured
by using Arrhenius plot. The degradation rate constant
(k25) at 25°C was calculated and found to be 5.723 × 10-4
week-1. Equation 2 was used to calculate the expiry date
of formula 13 which was 3.5 years.[42,48]
0.104
t10 % =
K 25
In this study, the dissolution rate profile of the stored
tablets was also checked after six months, whereby it
showed an insignificant difference (P > 0.05). In addi-
tion, there were no physical changes in the appearance
of the tablets at all temperatures after six months of
observation.
Effect of light (photosensitivity)
The sensitivity of the drug to light was studied on the
selected formula 13 for both uncoated and coated
forms so as to distinguish the difference in the degree of
decomposition of the drug in these two forms and the
degree of protection provided by the coating to the drug.
The constant rate values and the t10% of the drug in both
uncoated and coated forms were calculated, as shown in
Table 4. It was discovered that there was a significant dif-
ference (P < 0.05) in the degree of decomposition of drug
between uncoated and coated forms, thereby indicat-
ing that Eud L100 coating layer had protected the drug
from being decomposed by light. However, the amount
of drug lost after six months was very small, which was
only 1.465% w/w and 0.735% w/w for the uncoated and
Table 3.  Degradation rate constant (K) of mebeverine HCl of the
selected formula (13) at different temperatures.
Temp. (°C) K (week−1)
40 7.728 × 10−4
50 9.607 × 10−4
60 12.042 × 10−4
Table 4.  Degradation rate constant (K) and t10% of mebeverine HCl for
uncoated and coated tablets of the selected formula (13) by light.
F13 K (month−1) t10% (months)
Uncoated 11.26 × 10−3 9
Coated 5.66 × 10−3 18.4
coated forms, respectively. An insignificant change
(P > 0.05) was observed upon checking the dissolution
rate and appearance of tablets after six months.
Conclusion
The results indicate that an orally modified colon-
targeted tablet, comprising a core containing mebev-
erine HCl, Eud RL 100 (7% w/w) and pectin (6% w/w)
and an outer shell of Eud L 100, has the best release
properties.
In addition, Eud RL 100 and EC mixture is able to pro-
duce a good control to the release of drug as the ratio of
Eud RL 100 increases in both coated and uncoated forms,
i.e. when the concentration of Eud RL 100 increases with
a consistent concentration of EC due to its susceptibility
(2) to swelling. Eud RL 100 is able to provide a better control-
ling effect than EC when they are used alone in the matrix
of the coated tablets. This can be explained on the basis
that Eud RL 100 has a higher pH independent property
and swelling capability than that of EC.
For the uncoated formulations, the mixture of Eud RL
100 and EC at different ratios has proved to fail in control-
ling the drug release in the gastric fluids. This is due to
the incomplete swelling, the burst effect, and the high
drug solubility.
Pectin has shown to produce a weaker colon-targeting
efficiency in uncoated tablets compared to that of the
coated tablets. This is because of the high solubility,
incomplete gel formation and potent destruction of pec-
tin by the acidic fluids. Moreover, pectin has shown to
have better binding properties than sodium alginate in
the gastric media as the latter is more sensitive to acidic
conditions.
Finally, Eud L 100, as a coat among the different types
of coating materials being tested, has shown to produce
the best colon targeting effect. This could be due to the
delayed dissolution of the polymer in the artificial fluids
until it reaches pH 6 upwards.
Declaration of interest
The authors would like to thank the Institute of
Postgraduate Studies, Universiti Sains Malaysia, for
providing financial assistance. The authors report no
conflicts of interest. The authors alone are responsible
for the content and writing of the paper.
References
1. Nykänen P, Lempää S, Aaltonen ML, Jǖrjenson H, Veski  P,
Morvola  M. Citric acid as excipient in multiple-unit enteric-

coated tablets for targeting drugs on the colon. Int J Pharm
2001;229:155–162.
2. Minko T. Drug targeting to the colon with lectins and neoglyco-
conjugates. Adv Drug Deliv Rev 2003;56:491–509.
3. Fukui E, Miyamura N, Uemura K, Kobayashi M. Preparation of
enteric coated timed-release press-coated tablets and evaluation
of their function by in vitro and in vivo tests for colon targeting.
Int J Pharm 2000;204:7–15.
4. Liu L, Fishman ML, Kost J, Hicks KB. Pectin-based systems
for colon-specific drug delivery via oral route. Biomaterials
2003;24:3333–3343.
5. Yang L, Chu JS, Fix JA. Colon-specific drug delivery: New
approaches and in vitro/in vivo evaluation. Int J Pharm
2002;235:1–15.
6. Pitarresi G, Casadei MA, Mandracchia D, Paolicelli P, Palumbo
FS, Giammona G. Photo-cross linking of dextran and polyaspar-
tamide derivatives: A combination suitable for colon-specific
drug delivery. J Control Release 2007;119:328–338.
7. Yang L, James S, Chu and Joseph AF. Colon-specific drug deliv-
ery: New approaches and in vitro/in vivo evaluation. Int J Pharm
2002;235:1–15.
8. Marvola M, Nykäanen P, Rautio S, Isonen N, Autere AM. Enteric
polymers as binders and coating materials in multiple-unit site-
specific drug delivery systems. Eur J Pharm 1999;7:259–267.
9. Azarmi S, Farid J, Nokhodchi A, Bahari-Saravi SM,
Valizadeh H. Thermal treating as a tool for sustained release of
Indomethacin from Eudragit RS and RL matrices. Int J Pharm
2002;246:171–177.
10. Vergnaud JM. Controlled drug release from oral dosage forms.
London: Ellis Harwood Limited; 1993.
11. Lachman L, Lieberman HA, Kanig JL. The theory and practice of
industrial pharmacy. Philadelphia: Lea and Febiger; 1986.
12. Rey H, Wagner KG, Wehrlé P, Schmidt PC. Development of
matrix-based theophylline sustained-release micro tablets. Drug
Dev Ind Pharm 2000;26:21–26.
13. Eudragit RL and RS data sheets. Darmstadt: Röhm Pharma
GmbH: 1991
14. Pignatello R, Ferro M, Guidi GD, Salemi G, Vandelli MA,
Guccione  S, Geppi M, Forte C, Puglisi G. Preparation, char-
acterization and photosensitivity studies of solid dispersions
of diflunisal and Eudragit RS100® and RL100®. Int J Pharm
2001;218:27–42.
15. Omari DM, Sallam A, Abd-Elbary A, El-Samaligy M. Lactic acid-
induced modifications in films of Eudragit RL and RS aqueous
dispersions. Int J Pharm 2004;274:85–96.
16. Eudragit L and S data sheets. Darmstadt: Röhm Pharma GmbH:
1991.
17. Moustafine RI, Kemenova VA, Mooter GV. Characteristics of inter
polyelectrolyte complexes of Eudragit E 100 with sodium alginate.
Int J Pharm 2005;294:113–120.
18. Moustafine RI, Zaharov IM, Kemenova VA. Physicochemical
characterization and drug release properties of Eudragit® E PO/
Eudragit® L 100-55 inter-polyelectrolyte complexes. Eur J Pharm
Biopharm 2006;63:26–36.
19. Moustafine RI, Margulis EB, Sibgatullina LF, Kemenova VA,
Mooter GV. Comparative evaluation of inter-polyelectrolyte com-
plexes of chitosan with Eudragit L100 and Eudragit L100-55as
potential carriers for oral controlled drug delivery. Eur J Pharm
Biopharm 2008;70:215–225.
20. Sriamornsak P, Sungthongjeen S. Modification of theophyl-
line release with alginate gel formed in hard capsules. AAPS
PharmSciTech.2007;8(3)Article 51.
21. Toti US, Aminabhavi TM. Different viscosity grade sodium algi-
nate and modified sodium alginate membranes in pervapora-
tion separation of water + acetic acid and water + isopropanol
mixtures. J Membr Sci 2004;228:199–208.
22. Gao C, Liu M, Chen J, Zhang X. Preparation and controlled degra-
dation of oxidized sodium alginate hydrogel. Polym Degrad Stabil
2009;94:1405–1410.
23. Kenyon DA, Lerner CJ, Landau EI, Strauss I, Caron E,
Penhasi  D, Rubinstein A, Wilding IR. The use of scintigra-
phy to provide ‘proof of concept’ for novel polysaccharide
Mebeverine HCl colon-targeted tablets   341
preparations designed for colonic drug delivery. Pharm Res
1997;14:103–107.
24. Semdé R, Amighi K, Devleeschouwer MJ, Moes AJ. Studies
of pectin HM: Eudragit® RL: Eudragit® NE film-coating for-
mulations intended for colonic drug delivery. Int J Pharm
2000;197:181–192.
25. Li D, McHugh MA. Solubility behavior of ethyl cellulose in super-
critical fluid solvents. J Supercrit Fluids 2004;28:225–231.
26. Crowley MM, Schroeder B, Fredersdorf A, Obara S, Talarico M,
Kucera S, McGinity JW. Physicochemical properties and mecha-
nism of drug release from ethyl cellulose matrix tablets prepared
by direct compression and hot-melt extrusion. Int J Pharm
2004;269:509–522.
27. Builders PF, Kunle OO, Okpaku LC, Builders MI, Attama AA,
Adikwu MU. Preparation and evaluation of mucinated sodium
alginate micro-particles for oral delivery of insulin. Eur J Pharm
Biopharm 2008;70:777–783.
28. Haznedar S, Dortunc B. Preparation and in vitro evaluation of
Eudragit microspheres containing acetazolamide. Int J Pharm
2004;269:131–140.
29. Al-Taani BM, Tashtoush BM. Effect of microenvironment pH
of swellable and erodible buffered matrices on the release
characteristics of diclofenac sodium. AAPS Pharm Sci Tech
2003;4:article 43.
30. Brittain HG. Analytical profiles of drug substances and excipients.
California: Elsevier Science; 2002.
31. Duspatalin® Retard 200 mg capsules, available worldwide from
the website: /products/gastroentero/Duspatalin.
32. Sameh MA, Abdel-Hady SE, El-Shamy AA, El-Dessouky HF.
Formulation of an antispasmodic drug as a topical local anes-
thetic. Int J Pharm 2006;326:107–118.
33. Omaimah MN. In vitro adsorption of mebeverine hydro-
chloride onto kaolin and its relationship to pharmacologi-
cal effects of the drug in vivo. Pharmaceutica Acta Helvetiae
1997;72:11–21.
34. Dai N, Cong Y, Yuan H. Prevalence of irritable bowel syndrome
among undergraduates in Southeast China. Digest Liver Dis
2008;40:418–424.
35. British Pharmacopoeia BP. London: British Pharmacopoeia
Commission; 2004.
36. United States Pharmacopeia and United States Pharmacopeial
Convention USP 27. Philadelphia: United States Pharmacopeial
Convention; 2003.
37. Orlu M, Cevher E, Araman A. Design and evaluation of colon spe-
cific drug delivery system containing flurbiprofen microsponges.
Int J Pharm 2006;318:103–117.
38. Kuksal A, Tiwary AK, Jain NK, Jain S. Formulation and in
vitro, in vivo evaluation of extended- release matrix tab-
let of Zidovudine: Influence of combination of hydrophilic
and hydrophobic matrix formers. AAPS PharmSciTech
2006;7(1):Article 1.
39. Reddy KR, Mutalik S, Reddy S. Once-daily sustained-release
matrix tablets of nicorandil: Formulation and in vitro evaluation.
AAPS Pharm Sci Tech 2003;4:Article 61.
40. Lopes CM, Lobo JMS, Pinto JF, Costa PC. Compressed matrix
core tablet as a quick/slow dual-component delivery sys-
tem containing Ibuprofen. AAPS Pharm Sci Tech 2007;8:
Article 76.
41. Patrick JS. Martin’s physical pharmacy and pharmaceutical
science chemical; physical chemical and biopharmaceutical
principles in the pharmaceutical sciences. 5th ed. Philadelphia:
Lippincott Williams & Wilkins; 2006.
42. Pham AT, Lee PI. Probing the mechanism of drug release
from hydroxyl propyl methyl cellulose matrices. Pharm Res
1994;11:1379–1384.
43. Yang LB, Fassihi R. Examination of drug solubility, polymer type,
hydrodynamics and loading dose on drug release behavior from
a triple-layer asymmetric configuration delivery system. Int J
Pharm 1997;155:219–229.
44. Pather SI, Russell I., Syce JA, Neau SH. Sustained release theo-
phylline tablets by direct compression. Part 1: Formulation and
in vitro testing. Int J Pharm 1998;164:1–10.
342   G. Z. Abdullah et al.
45. Wakerly Z, Fell JT, Attwood D, Parkins DA. In vitro evaluation
of pectin-based colonic drug delivery systems. Int J Pharm
1996;129:73–77.
46. Kubo W, Konno Y, Miyazaki S, Attwood D. In situ gelling pectin
formulations for oral sustained delivery of paracetamol. Drug
Dev Ind Pharm 2004;30:593–599.
47. Pornsak S, Sungthongjee S. Modification of theophylline release
with alginate gel formed in hard capsules. AAPS Pharm Sci Tech
2007;8:Article 51.
48. Ellison T, Snyder A, Bolger J, Okun R. Metabolism of orphen-
adrine citrate in man. J Pharmacol Exp Ther 1971;176:
284–295.
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