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Influence of micro-environmental pH on the gel layer behavior and

release of a basic drug from various hydrophilic matrices

Article  in  Journal of Controlled Release · April 2005

DOI: 10.1016/j.jconrel.2004.12.015 · Source: PubMed

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 Journal of Controlled Release 103 (2005) 499 – 510
www.elsevier.com/locate/jconrel

Influence of micro-environmental pH on the gel layer behavior and

release of a basic drug from various hydrophilic matrices
Manthena V.S. Varma, Aditya M. Kaushal, Sanjay Garg*
National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, SAS Nagar, Punjab 160 062, India
Received 29 May 2004; accepted 20 December 2004
Available online 25 January 2005

Abstract

The purpose of this investigation is to understand the influence of gastrointestinal (GI) pH on the gel layer formation and its
dynamics for various hydrophilic/swellable matrices, in the process of developing a pH-independent controlled release system
for a basic drug, oxybutynin hydrochloride (OXB). Cylindrical matrices (8-mm diameter) without and with fumaric acid, were
readily prepared by direct compression. Formulations were evaluated for in vitro drug release, and gel layer dynamics was
studied by viscosity measurements and texture profiling analysis. In the in vitro drug release study, OXB, which shows pH-
dependent solubility, showed faster release from all the matrices in pH 1.2 medium. Release rates enhanced to a lesser extent
with change of medium from pH 6.8 to pH 1.2, for HPMC polymer matrices. Anionic polymer matrices showed drastic
differences in the release rates when medium was changed from pH 6.8 to pH 1.2. Addition of fumaric acid to matrices
demonstrated pH-independent drug release, which was attributed to the micro-environmental pH manipulation within the
hydrated gel layer. Viscosity and texture profiling studies revealed that saturation solubility of drug at swelling front play a
major role in the pH-dependent drug release from HPMC matrices, while both saturation solubility and the altered gel
consistency as a function of pH are involved with anionic polymer matrices. Presence of fumaric acid in HPMC matrices
showed efficient retardation and pH-independent drug release. In conclusion, understanding the influence of GI physiological
pH on the gel layer dynamics and manipulating the micro-environmental pH provides efficient and predictable in vivo
performance from these swellable cylindrical matrices.
D 2004 Elsevier B.V. All rights reserved.

Keywords: Hydrophilic/swellable matrices; pH-independent drug release; Gel layer dynamics; Texture profiling; Oxybutynin hydrochloride

1. Introduction

The goal of controlled release (CR) delivery

systems is to provide desirable delivery profile that
* Corresponding author. Present affiliation: School of Phar-
macy, The University of Auckland, Private Bag 92-019, Auckland, can achieve predictable plasma levels. However,
New Zealand. Tel.: +64 9 373 7599x82836; fax: +64 9 367 7192. physiological variables in GI tract including GI pH,
E-mail address: s.garg@auckland.ac.nz (S. Garg). gastric residence time, intestinal motility and the GI
0168-3659/$ - see front matter D 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jconrel.2004.12.015
500 M.V.S. Varma et al. / Journal of Controlled Release 103 (2005) 499–510
contents, may alter the in vivo drug release perform-
ance of peroral CR systems [1]. Protic and ampho-
lytic drugs demonstrate pH-dependent solubility
profiles based on their ionizable groups. Thus, drug
release rate from controlled release matrices, espe-
cially for these drugs, may vary as a function of their
movement into various segments of GIT, leading to
inefficient drug delivery and high inter-subject
variability.
Several attempts based on the incorporation of
acidic excipients in the matrix, which keep the pH
within the system and hence the solubility of ionizable
drugs constant, irrespective of the dissolution
medium, proved efficient drug release from matrices.
Gabr showed pH-independent drug release of papa-
verine HCl from cellulose acetate and bees wax inert
matrix tablets in the presence of an organic acid [2].
Streubel et al. studied the effect of fumaric acid, sorbic
acid and adipic acid on HPMC and ethyl cellulose
matrices and demonstrated pH-independent release of
verapamil HCl with fumaric acid containing HPMC
matrices [3]. Vinopocetine release from HPMC
matrices showed a linear relationship between the
release rates and the proportion of citric acid added to
the matrix [4]. Tatavarti et al. modulated matrix
micro-environmental pH by incorporating acidic
polymers and thus enhanced the local solubility and
demonstrated acidic polymer concentration dependent
micro-environmental pH and the release of papaverine
HCl [5].
Incorporation of acidic excipients is a more useful
approach for basic drugs because, (i) solubility of
basic drugs decreases exponentially with increase in
pH and thus may precipitate within the matrix as it
proceeds into lower part of intestine, leading to
incomplete drug release, (ii) drug release being a
function of drug solubility, release rates fall as the
matrix moves to higher pH range, thereby introducing
variability associated with GI transit.
Swellable/hydrophilic matrices are characterized
by the formation of gel layer on the matrix surface.
Phenomena that govern gel layer formation and
consequent drug release rate are water penetration,
polymer swelling, drug dissolution, diffusion and
matrix erosion. This gel layer formation and its
stability that defines the kinetics of drug delivery
from matrix systems, is controlled by the concen-
tration, viscosity and chemical structure of the
polymer(s) [6]. Apart from the physicochemical
properties of the drug (pK a and solubility), the
polymer dissolution rate is also a dominant process
in drug release, which in turn is dependent on the
matrix shape, dimension, type of dissolution medium
and the polymer [7,8]. A swelling and an erosion
front form during the swelling process of hydrophilic
matrices. The drug is soluble completely or to a
certain extent in the gel layer based on the saturation
solubility and the volume of medium available at the
moving fronts. Thus, when a drug has a finite
solubility, a layer of undissolved drug can be
detected in the gel [9]. The position of this layer,
separating the undissolved drug from dissolved drug
gel region, called diffusion front, is thus highly
dependent on the media conditions. Drugs demon-
strating highly pH-dependent solubility thereby show
complex gel layer behavior as the matrix formula-
tions travel down the GIT. Difference in the gelation
properties of the polymers as a function of media pH
further complicates the drug release process and its
predictability.
The present investigation was an attempt to
understand the influence of GI physiological pH on
the gel layer formation and its dynamics; and on the
drug release characteristics of a basic drug, OXB,
from non-ionic and anionic hydrophilic matrices. We
also studied the influence of manipulating micro-
environmental pH of the hydrating swollen layer on
the gel layer dynamics and ultimately the drug release
characteristics. Two non-ionic polymers (hydroxy-
propyl methylcellulose, METHOCEL K4M and
K15M) and two anionic polymers (carbopol 971P
and xanthan gum) were compared with respect to
change in mechanisms of drug release and the
physical structure of matrix in GI physiological pH
conditions based on drug release, viscosity and texture
profiling studies.
2. Materials and methods
2.1. Materials
Oxybutynin hydrochloride (USP) was received as
gratis sample from Unichem Lab. Ltd. (Mumbai,
India). Hydroxypropyl methylcellulose (HPMC) pol-
ymers were supplied by Dow Chemicals (Colorcon
 M.V.S. Varma et al. / Journal of Controlled Release 103 (2005) 499–510
Asia Pvt. Ltd., Mumbai, India) as METHOCEL K4M
and K15M having nominal viscosity of 4000 and
15,000 cps (2% aqueous solutions), respectively.
Carbopol 971P (CP) (The BFGoodrich Co., Cleve-
land, OH) and xanthan gum (XG) (Xantural 75,
Waterfield, UK) were received as gift samples from
Signet, (Mumbai, India). Fumaric acid was procured
from Sigma Chemicals (MO, USA). Magnesium
stearate (Mallinckrodt, USA), Aerosil 200 (Degussa
AG, Frankfurt), and directly compressible lactose
(Flowlac 100, Meggle GMBH, Wasserburg) were
obtained from Unichem Lab. (Baddi, India). Acetoni-
trile HPLC grade and methanol HPLC grade were
obtained from JT Baker (Mexico) and Ranbaxy Fine
Chem. Ltd. (SAS Nagar, India), respectively. All other
chemicals and reagents used were of analytical grade.
2.2. Solubility of OXB
Solubility of OXB was determined in simulated
gastric fluid without enzymes (SGF pH 1.2), pH 6.8
phosphate buffer and in pH 10.2 phosphate buffer, by
adding an excess of drug to the media (n=3). After
equilibrating on shaker water bath (37F1 8C) for 24 h,
samples were filtered through 0.22 Am filter and the
drug concentration in filtrate was determined by
HPLC.
2.3. Tablet preparation
The tablets were made up of 5% OXB, polymers
(varying proportions of K4M, K15M, CP and XG),
fumaric acid (FA) (varying proportions), 1% magne-
sium stearate, 0.25% aerosil and lactose q.s. as filler.
Blending of the components was carried out in a
laboratory model drum blender (Kalweka, Mumbai,
India) and the blend was compressed using 8 mm
diameter, flat faced die and punches (CMS-15,
Cadmach tablet press, India). Hardness for all the
formulations was adjusted in the range of 11–14 Kp
(TBH20, Erweka Instruments, CT, USA) and the
weight of each tablet was 200F4 mg. Batch size for
each formulation was 100 g (500 tablets).
2.4. Dissolution studies
The dissolution behavior of OXB from various
formulations was carried out on USP rotating basket
501
apparatus (Electrolab, Mumbai, India). The operating
speed of the dissolution basket was 100 rpm, media
used were 500 ml of SGF (pH 1.2) or pH 6.8
phosphate buffer maintained at 37F0.5 8C. Progress
of the dissolution was monitored by withdrawing
samples at predetermined intervals and assayed by
HPLC. The data were indicated as meanFS.D. of
three replicates for each dissolution.
The drug release data was analyzed and interpreted
with the simple power law expression, which can best
describe the kinetics of drug release from swellable
hydrophilic matrices [10,11].
Mt
¼ kt n ð1Þ
Ml
where M t /M l, is the fraction of drug release at time t,
k, the kinetic constant and n, the release exponent that
characterizes the mechanism of drug release. For a
cylindrical matrix, values of n=0.45 indicate Fickian
drug release, 0.45bnb0.89 indicate an anomalous
(non-Fickian) release, whereas values of n=0.89
indicate case II transport kinetics. Fickian diffusional
release occurs by molecular diffusion of the drug due
to a chemical potential gradient. Case II relaxational
release is the drug transport mechanism associated
with stresses and state transition in hydrophilic glassy
polymers, which swell in water or biological fluids.
The two phenomena controlling drug release from
swellable matrices are considered additive [12,13].
Mt
¼ k1 t m þ k2 t 2m ð2Þ
Ml
where the first term is contribution of Fickian
diffusion and the second term is the case II relaxa-
tional contribution. m value of 0.45 was taken based
on the aspect ratio of the matrices. The ratio of
relaxational over Fickian contribution is given by
[10,12,14]
R k2
¼ tm : ð3Þ
F k1
To describe the shape of release profile, data were
also fitted to Weibull distribution [15].


M ¼ 1  exp  at b ð4Þ
where, M is accumulated fraction of drug in solution
at time t. a is a scale parameter given as k1/(1h) and
502 M.V.S. Varma et al. / Journal of Controlled Release 103 (2005) 499–510
b is shape parameter given by (1h). k1 is a constant
not dependent on time with units (time)h1 and h is a
pure number.
2.5. Viscosity determinations
Polymer solutions of K4M, K15M, CP and XG
were prepared by thorough dispersion of 1%w/v
polymer in buffers of pH 1.2, 3.8, 5.2 and 6.8, under
agitation. Solutions were maintained at 37F1 8C for
48 h to ensure complete hydration. Viscosity was
performed on a cup and bob viscometer (model DV-
III+, Brookfield, MA). All measurements were carried
out at room temperature (24F2 8C). Apparent
viscosities were measured at a shear rate of 189 S1
after allowing the solutions to equilibrate for 10 min.
The mean of not less than three replicates was taken to
represent viscosity.
To study the effect of fumaric acid on the pH and
viscosity of polymer solutions, 0.1%w/v of fumaric
acid was added to polymer solutions (in pH 6.8) and
pH and viscosity were recorded after equilibrating for
48 h.
2.6. Texture Profiling on hydrated matrices
Gel layer formation and its dynamics as a function
of time was evaluated by texture profiling analysis
(Texture Analyzer, TA XT2i, Stable Micros Systems,
UK). Texture profiling for hydrated matrices of four
different polymers with and without FA in different
dissolution media were carried by the procedure
reported earlier, with minor modifications [16,17].
One planar base of each tablet was sealed off by fixing
the tablet on to a glass coverslip using a fixer solution
(Fevikwik, Fevi India). Each sealed tablet was then
placed in the basket assembly and proceeded as
mentioned in dissolution studies. This allows medium
ingression from all the directions and simulates the
actual process of gel dynamics that occurs in the
dissolution studies, as the tablets freely move in the
basket. At predetermined time intervals, tablets (n=3)
were removed and subjected to texture analysis. A
flat-tipped steel probe, 2 mm in diameter, was
connected to a force transducer that measured the
force of resistance encountered by the probe during
advancement into the sample. Test parameters fixed
for all the samples included, pre-test speed, 1 mm s1;
test speed and post-test speed 0.2 mm s1; maximum
compression force, 40 N; and auto trigger force 0.005
N. Data were captured at a rate of 200 points s1 by
Texture Expertk for Windows software.
2.7. HPLC analysis
Chromatography was carried out on Shimadzu
HPLC equipped with Class VP software for data
processing. Samples were analyzed at 25 8C on a 4.6-
mm250-mm 5 Am cyano column (Hypersil BDS
CPS) attached to a Hypersil BDS CPS precolumn.
UV–Vis detector (SPD-10A VP) was set at 203 nm
and mobile phase was pumped at a flow rate of 1.5
ml/min. Mobile phase consisting of Solvent A and
acetonitrile in the proportion of 60:40 was prepared,
where Solvent A is a mixture of water, methanol and
triethylamine in the proportion of 3200 ml, 800 ml
and 0.9 ml, respectively, with pH 3.5 (adjusted with
phosphoric acid). Mobile phase was filtered through
0.45 Am nylon filter (Millipore) and deaerated in
ultrasonic bath (Branson sonicator). Sample injections
of 50 Al each were made automatically using
autosampler (SIL-10AD VP).
3. Results and discussion
3.1. pH-dependent dissolution of OXB
OXB, a monoprotic base with pK a 8.04, showed
pH-dependent solubility in the GI pH range (Fig. 1).
The solubility of OXB is 754F25.2 mg ml1 at pH
1.2, 1.24F0.58 mg ml 1 at pH 6.8, and
0.021F0.0015 mg ml1 at pH 10.2. Based on the
pK a and the intrinsic solubility of the drug (saturation
solubility above pK a), theoretical solubility profile
was generated [18]. Theoretical and experimental
data, which is in agreement to the literature values
[19], indicated exponential decline in the solubility of
OXB from pH 1.2 to pH 6.8.
A remarkable difference in the drug release from
all the hydrophilic matrices was observed in pH 1.2
SGF and pH 6.8 phosphate buffer. Fig. 2 shows that
K4M, K15M, CP and XG at 75%, 50%, 15% and
10%w/w proportions, respectively, controlled OXB
release in pH 6.8 phosphate buffer. These polymer
concentrations were optimized in the preliminary
 M.V.S. Varma et al. / Journal of Controlled Release 103 (2005) 499–510 503

100000
formulations but was variable from polymer-to-
Solubility of OXB (mg/ml)

10000 polymer matrices. The enhanced release in pH 1.2

1000 could be due to (i) high solubility of OXB at lower pH
and/or (ii) pH-dependent swelling and gel layer
100
dynamics of hydrophilic polymers. HPMC polymers
10 (K4M and K15M) showed relatively less hastening of
1
pKa = 8.04 release kinetics than shown by CP and XG. In case of
HPMC matrices (K4M, 50%w/w), approximately
0.1
34% and 10% of the drug was released after 2 h in
0.01 SGF and pH 6.8 phosphate buffer, respectively. After,
0 2 4 6 8 10 12 14
6 h, 64.2% of the drug was released in pH 1.2
pH
medium, while only 27.6% was released in phosphate
Fig. 1. Theoretical (E) and experimental (5) pH solubility profiles buffer. However, CP and XG polymeric matrices
of OXB HCl at 37 8C. Theoretical profile was generated by the showed quite a faster release in SGF over pH 6.8
equation S/S o=10+pK apH+1, where S and S o are solubilities at test
phosphate buffer. The reason for this could be the
pH and at any pH above pK a, respectively. S o was determined
experimentally at pH 10.2 and pK a value of 8.04 was taken from ionic nature of these polymers where pH may
literature [19]. Experimental data indicate meanFS.D. of three influence the swelling behavior and the gel layer
independent determinations. dynamics, apart from pH-dependent solubility of
OXB.
studies, to obtain near zero-order release however, Fig. 3 illustrates the R/F ratio values versus fraction
with incomplete release (data not shown). OXB released from the matrices for all four hydrophilic
release in pH 1.2 was relatively faster from all the polymers, in both pH 6.8 and pH 1.2 media. Model was

a) b)
75% K4M (pH 1.2) 50% K15M (pH 1.2)
100 100
75% K4M + 10 % FA (pH 6.8) 50% K15M + 10% FA (pH 6.8)
75% K4M + 5% FA (pH 6.8) 50% K15M + 5% FA (pH 6.8)
80 75% K4M (pH 6.8) 80 50% K15M (pH 6.8)
% Release

% Release

60 60

40 40

20 20

0 0
0 2 4 6 8 10 12 0 2 4 6 8 10 12
Time (hrs) Time (hrs)

c) d)
15% CP (pH1.2) 10% XG (pH 1.2)
100 100
15% CP + 10% FA (pH 6.8) 10% XG + 10% FA (pH 6.8)
15% CP + 5% FA (pH 6.8) 10% XG + 5% FA (pH 6.8)
80 15% CP (pH 6.8) 80 10% XG (pH 6.8)
% Release

% Release

60 60

40 40

20 20

0 0
0 2 4 6 8 10 12 0 2 4 6 8 10 12
Time (hrs) Time (hrs)

Fig. 2. Effect of dissolution medium pH and the presence of fumaric acid in the matrices on OXB release from (a) 75% HPMC K4M, (b) 50%
HPMC K15M, (c) 15% carbopol 971P, and (d) 10% xanthan gum matrices.
504 M.V.S. Varma et al. / Journal of Controlled Release 103 (2005) 499–510

3.0 K4M (pH 6.8)

K4M (pH 1.2) high leading to faster and usually complete release.
K15M (pH 6.8) Ideally, organic acids with high acidic strength (low
2.5 K15M (pH 1.2)
CP (pH 6.8) pK a values) and relatively low solubility in lower pH
2.0
CP (pH 1.2) range are suitable as they can provide low pH in the
XG (pH 6.8)
XG (pH 1.2) matrix for longer periods even at low proportions.
R/F

1.5 Because of their high solubility in high pH range,

organic acids can act as pore formers at high pH
1.0 values, thus low proportions are always desirable.
With these fundamental requirements, fumaric acid
0.5
was selected for our studies, which has a pK a1 3.03
0.0
and pK a2 4.54 (25 8C) and aqueous solubility of 6.3
0 0.1 0.2 0.3 0.4 0.5 0.6 mg ml1 (25 8C) [20].
Fraction Released Addition of fumaric acid to hydrophilic matrices
Fig. 3. Ratio of relaxational over Fickian contribution versus
significantly increased the drug release in pH 6.8
fraction released for non-ionic (K4M, K15M) and anionic (CP, XG) phosphate buffer (Fig. 2). The increase in release from
polymer matrices in pH 6.8 and pH 1.2 dissolution media. each was further found to be dependent on the amount

fitted up to 60% of drug release. HPMC polymers

showed no significant difference in terms of mecha- Table 1
Mathematical modeling and drug release kinetics from hydrophilic
nism with change in media pH. Relaxational process
matrices without (in different media) and with fumaric acid, fitted to
predominated for most of the drug release over Weibull distributiona
Fickian diffusion with K15M matrices, while K4M
Formulation a b hb K1 R2
matrices showed equal contribution of both the (dissolution medium)
mechanisms (R/F c1). CP matrices in pH 6.8 showed 75% K4M (pH 6.8) 0.056 1.038 0.038 0.058 0.997
equal contribution of both the phenomenon but diffu- 75% K4M+5% FA 0.108 0.896 0.104 0.097 0.997
sional release predominated in the acidic medium. XG (pH 6.8)
polymer matrices showed high relaxational contribu- 75% K4M+10% FA 0.182 0.801 0.199 0.146 0.999
tion in pH 1.2 but Fickian diffusion in pH 6.8. (pH 6.8)
75% K4M (pH 1.2) 0.201 0.809 0.191 0.163 0.997
XG matrices showed a more homogenous release 50% K15M (pH 6.8) 0.067 0.880 0.120 0.059 0.997
(b=1, h=0) in pH 1.2 than in pH 6.8, while K4M 50% K15M+5% FA 0.098 0.934 0.066 0.092 0.990
matrices showed homogenous release in 6.8 pH. K4M (pH 6.8)
matrices showed an exponential release (bb1, 0bhb1) 50% K15M+10% FA 0.206 0.870 0.130 0.179 1.000
with a steeper initial burst in pH 1.2 (Table 1). This (pH 6.8)
50% K15M (pH 1.2) 0.202 0.942 0.058 0.190 0.996
can be attributed to high solubility and thus fast 15% CP (pH 6.8) 0.100 0.854 0.146 0.085 0.988
dissolution of the drug from the matrix surface, well 15% CP+5% FA 0.125 1.018 0.018 0.127 0.988
before the formation of a matured gel layer. The rate (pH 6.8)
constant k1 increased in pH 1.2 from all the matrices, 15% CP+10% FA 0.258 0.868 0.132 0.224 0.986
however, large differences in the rate constant at pH (pH 6.8)
15% CP (pH 1.2) 0.350 0.780 0.220 0.273 0.978
1.2 and 6.8 were observed for CP and XG matrices. 10% XG (pH 6.8) 0.068 0.832 0.168 0.056 0.982
10% XG+5% FA 0.151 0.930 0.070 0.140 0.997
3.2. Influence of fumaric acid on OXB release: (pH 6.8)
modulation of micro-environmental pH 10% XG+10% FA 0.318 0.996 0.004 0.317 0.997
(pH 6.8)
10% XG (pH 1.2) 0.340 1.010 0.010 0.343 1.000
Addition of organic acids to the formulation could a
create a constant acidic micro-environment inside the Drug release data was fitted to Eq. (4) using Sigmastat 2.03
software (SPSS, USA).
gel layer, irrespective of the surrounding dissolution b
0bhb1, rate of release is monotonically decreasing with time;
medium. The pH inside the gel layer is expected to be hb0, increasing initially and decreasing afterwards; hc1, homoge-
acidic and thus the solubility of basic drug will be neous release [15].
 M.V.S. Varma et al. / Journal of Controlled Release 103 (2005) 499–510
of fumaric acid. However, resulting release profiles of
matrices with 10% fumaric acid (in pH 6.8 phosphate
buffer) almost overlapped with the release of corre-
sponding matrices without fumaric acid, in pH 1.2
SGF. This is in good agreement with the above
discussed hypothesis that organic acids maintain a
constant micro-environmental pH of the matrices/gel
layer. The reason for lesser release of drug from
matrices with 5%w/w fumaric acid could be that the
amount of fumaric acid available as the buffer ingresses
into the formulation may not be sufficient to maintain
the micro-environmental pH to a level as provided by
10%w/w. It should be noted that pH lowering by
fumaric acid is also influenced by the buffering
capacity of the medium. Streubel et al. reported fumaric
acid concentration independent drug release of vera-
pamil hydrochloride from HPMC matrices, however
the concentrations used in the study were much higher
than those used in the present study [3].
Further, to monitor the micro-environmental pH,
dissolution studies of HPMC K15M matrices with
fumaric acid (5% and 10%w/w) were carried out in pH
6.8 phosphate buffer containing either thymol blue
(0.001%w/v) or methyl red (0.001%w/v). Thymol blue
is red (pHb2.8) or yellow (pHN2.8) at different pH
ranges, while methyl red is red at acidic pH and yellow
above pH 5.8. In case of K15M matrices with 10%
fumaric acid, matrix core remained red in both media
and yellowish from the surface. It was also observed
that red and yellowish colored layers move towards the
center, as a function of time and the matrix core
remained red until 8 h in medium containing thymol
blue. In case of matrices with only 5%w/w fumaric
acid, tablet core remained red in only methyl red
medium at 1, 2, 4 and 6 h. Furthermore, monitoring of
pH of dissolution medium during dissolution showed
no deviation from pH 6.8F0.2. Concisely, this set of
experiments, indicated that 10%w/w fumaric acid
maintained the micro-environmental pH below 2.8
for at least 8 h while 5%w/w fumaric acid maintained
pH between 2.8 and 5.8 for at least 6 h. Increase in
release with further increase in fumaric acid proportion,
may occur not due to influence of micro-environmental
pH, but because of the leaching of fumaric acid from
the formulations [21,22]. As was observed with the
differences in release kinetics with change of pH from
6.8 to 1.2, the drug release rate increased to large extent
for matrices with CP and XG, when added with fumaric
505
acid. These results once again substantiate the hypoth-
esis that low pH influences the formation of gel layer
and its mechanical stability.
3.3. Viscosity of gelatinous layer
To further confirm the hypothesis of pH-dependent
gel layer behaviour, the viscosity studies were carried
out for 1%w/v solution of each polymer in media with
pH 1.2, 3.8, 5.2 and 6.8. When hydrophilic matrices
come into contact with water, they absorb water and
swell to form a gel, which serves as a barrier to drug
diffusion. Since movement of the drug solute through
the matrix system is diffusion controlled, it may be
expected from the Stokes–Einstein equation that the
drug release process will be inversely proportional to
the mechanical strength/viscosity of the gel layer.
Since gel layer behavior is both dynamic and gradient,
viscosity measurement could be difficult. Thus an
assumption was made that the bulk viscosities of the
diluted polymer solutions are indicative of the
diffusion resistance experienced by the solute.
The apparent viscosities of the polymer solutions at
various pH are presented in Fig. 4. Viscosities of
HPMC solutions were constant irrespective of solution
pH. HPMC polymers are non-ionic and therefore the
solubility and swelling behavior are not influenced by
pH. K15M solution (1%w/v) showed higher viscosity
350
K4M
K15M
300
Brookefield Viscosity (CPs)
CP971P
XG
250
200
150
100
50
0
0 2 4 6 8
pH
Fig. 4. pH viscosity profiles of 1%w/v solutions of non-ionic and
anionic hydrophilic polymers, after equilibration for 48 h (37 8C).
Open points indicate the data of pH and viscosities of corresponding
polymer solutions in pH 6.8 buffer, after addition of 0.1%w/v of
fumaric acid and equilibrating for 48 h (37 8C). Each data point
indicates meanFS.D. of three independent determinations.
506 M.V.S. Varma et al. / Journal of Controlled Release 103 (2005) 499–510

than K4M solution, which correlates to faster release
of OXB from matrices with K4M (75%w/w) versus
K15M (50%w/w), at pH 6.8 (Fig. 2). HPMC polymers
are giant macromolecules and have a great affinity for
water. When a polymer chain comes into contact with
water, polymer water interaction replaces polymer–
polymer attractions, and their hydrodynamic volumes
also increase [23,24]. High viscosity grade HPMCs are
made up of larger macromolecules and adopt more
extended configuration and therefore produce highly
viscous gel layer.
The viscosity of CP and XG were found to be
highly pH dependent with least viscosity at pH 1.2
and higher at pH 6.8. However, the viscosities of both
the polymers at pH 6.8 were higher than the
viscosities of HPMC polymers. This can be correlated
to greater retardation of OXB release with 10% and
15%w/w of XG and CP, respectively, compared to
50%w/w of K15M and 75%w/w of K4M. CP and XG
possessing carboxyl acid functional groups, have a
significant correlation between DE or MDT and
viscosity of polymer solutions in the corresponding
conditions was observed (Fig. 5). However, a trend
was seen for CP and XG polymers, where DE is high
at low viscosity and MDT is more when the viscosity
was high. Choeng et al. showed good correlation
between viscosities of HPMC solution and the T 50%,
at various polymer proportions [26]. However, HPMC
polymers showed no relation between viscosity and
the release behavior of basic drug from their matrices
in different pH conditions. These results indicate that
the enhanced OXB release from HPMC polymers at
a)
80 1
2 K4M K15M CP XG
2
1 1
60 2
1
2
DE

40 3
difference in the process of gel layer formation and its 3
3
mechanical stability as a function of pH. They are
unionized at acidic pH and thus have less of 20 3

intermolecular hydrogen-bonding. Viscosity rise was

very abrupt in case of CP, while for XG a gradual
0
increase in viscosity was observed from pH 1.2 to 6.8. 0 100 200 300
The stability of XG to change in pH is relatively high Viscosity of solution (Cps)
and can be attributed to the rod shape of the molecule, b)
its intermolecular hydrogen-bonding and to its pK a. 6.0
Addition of 0.1%w/v fumaric acid to the polymer
solutions in pH 6.8 buffer reduced the pH of all 3
3
3 3
5.0
polymer solutions to ~2, after 48 h of equilibration.
Apparent viscosities determined showed that fumaric
2
MDT

acid presence has no effect on the viscosity of HPMC 4.0 1

2
1 2
polymers, while viscosities of CP and XG drastically 1
reduced and matched the viscosities of simple 2
3.0
polymer solutions in the corresponding pH (Fig. 4).
These results indicate that the manipulation of micro- 1

environmental pH in HPMC matrices show no 2.0

influence on the gel layer dynamics. However, gel 0 100 200 300

layer of CP and XG matrices will be highly influenced Viscosity of solution (Cps)

by the pH of the medium or the presence of organic
acids in the matrix.
The dissolution efficiency (DE) and the mean
dissolution time (MDT), determined from the drug
release studies of matrices with and without 10%w/w
fumaric acid, were compared to analyze the influence
of viscosity on the drug release profile [11,25,26]. No
Fig. 5. Relationship between (a) dissolution efficiency and the
apparent viscosity, and (b) mean dissolution time and the apparent
viscosity of the polymer solutions. Key: 1, Viscosity in pH 1.2 and
drug release from control matrix (without fumaric acid) in pH 1.2
medium; 2, Viscosity in the presence of 0.1%w/v fumaric acid and
drug release of 10%w/w fumaric acid containing matrix in pH 6.8
medium; 3, Viscosity in pH 6.8 and drug release from control matrix
(without fumaric acid) in pH 6.8 medium.
 M.V.S. Varma et al. / Journal of Controlled Release 103 (2005) 499–510 507

pH 1.2 or from the matrix containing 10%w/w a)

Force (N)
fumaric acid was mainly due to the saturation 45.00
solubility difference at the swelling front and not CP XG K15M
40.00
due to the difference in the gel layer viscosity at
different pH. On the other hand, in the case of CP and 35.00

XG polymers, both the saturation solubility difference 30.00

at the swelling front and the difference in the gelation 25.00
of matrix and its stability leads to high release rates at 20.00
low pH range.
15.00

3.4. Texture profiling and gel layer dynamics of 10.00

swollen matrices 5.00

0.00
Yang et al. [16] and Pillay and Fassihi [17] 0.0 1.0 2.0 3.0 4.0
-5.00 Distance (mm)
demonstrated the potential and application of texture
analysis in characterization of the swelling behavior of b)
hydrophilic matrices. The advantage of this technique Force (N)
45.00
over other techniques (e.g. imaging analysis) is its CP XG K15M
simultaneous interpretation of gel layer growth and 40.00
the mechanical stability/consistency of the gel layer 35.00
formed for any drug–polymer matrix [9,27,28]. Fig. 6 30.00
shows the typical force–displacement (F–D) profiles
25.00
of three hydrophilic matrices (without and with
20.00
fumaric acid) after 1.5 h of hydration in pH 6.8
medium. It is obvious from the figure that the three 15.00
polymeric matrices have different degree of hydration 10.00
and swelling, and presence of acidic microenviron- 5.00
ment pH showed altered swelling behavior.
0.00
F–D profiles are quantitative indications of the 0.0 1.0 2.0 3.0 4.0
-5.00 Distance (mm)
polymer viscosity/resistance within the gel layer as a
function of distance. Gel layer thickness and the work Fig. 6. Representative force–distance plots of hydrated gel layer of
done against the resistance offered by the gel layer, as polymeric matrices (K15M 50%w/w, CP 15%w/w and XG 10%w/
determined from the F–D profiles, are represented as a w) (a) without fumaric acid and (b) with 10% fumaric acid, after 1.5
h of exposure to pH 6.8 phosphate buffer.
function of time in Fig. 7. In the control matrices
(without fumaric acid), K15M matrices showed con-
sistent increase in the gel layer thickness and the work with CP matrices. Gel layer thickness (i.e. diffu-
done with time in 6.8 pH medium. It showed an sional path length) and the stability of gel (depicted
increase of gel layer thickness from 1.76F0.11 mm at by work done) are two main components control-
0.5 h to 4.93F0.54 mm at 2 h and to 6.66F0.65 mm at ling drug release. However, with XG and CP
3 h. Similarly, work done, which is an indicative of gel matrices, even though both these parameters are
consistency changed from 11.88F0.56 N mm at 0.5 h less, showed more retardation in drug release with
to 45.43F3.05 N mm at 3 h. CP and XG matrices respect to HPMC polymeric matrix. Initial growth
showed gel layer thickness of 2.74F0.19 mm and in the gel layer thickness occurred fairly fast with
3.8F0.23 mm by the end of 2 h. XG matrices anionic polymers and not much change was
completely hydrated after 2 h, and K15M and CP after observed as a function of time. Gel consistency
3 h. showed a similar trend, indicating that these
For anionic polymer matrices, the change in gel polymers showed faster hydration and thus faster
layer dynamics was found to be less, especially matured gel layer.
508 M.V.S. Varma et al. / Journal of Controlled Release 103 (2005) 499–510

(a) (b)
8 K15M 8 K15M+FA

Gel layer thickness (mm)

Gel layer thickness (mm)
7 XG 7 XG + FA

6 CP 6 CP + FA

5 5
4 4
3 3
2 2
1 1
0 0
0 0.5 1 1.5 2 2.5 3 0 0.5 1 1.5 2 2.5 3
Time (hrs) Time (hrs)

(c) (d)
70 70
K15M K15M+FA
60 60

Workdone [N.mm]
Workdone [N.mm]

CP CP + FA
50 XG 50 XG + FA

40 40
30 30
20 20
10 10
0 0
0.5 1 1.5 2 3 0.5 1 1.5 2 3
Time (hrs) Time (hrs)

Fig. 7. Dynamic changes in the gel layer thickness (a, b) and the total work performed against the gel resistance (c, d) as a function of time for
HPMC (K15M), carbopol (CP) and xanthan gum (XG) matrices without (a, c) and with (b, d) fumaric acid. Work done against the resistance
offered by the gel layer was obtained as area under the F–D profiles. Data indicates meanFS.D. of three independent determinations.

The other reason for efficient retardation by CP and volume fraction in the gel layer because of which the
XG could be the contribution of ionic interactions gel layer consistency decrease to certain extent with
between drug and the anionic polymers. The presence increase in surface erosion [21].
of carboxyl functional groups may lead to OXB HCl– In case of anionic polymer matrices, presence of
anioinic polymer interactions which are further fumaric acid, showed a drastic effect on gel layer
dependent on ionization state of the functional groups dynamics, where both the gel layer thickness and the
[29,30]. In acidic environment, the carboxyl groups of work done against gel resistance were reduced, when
these polymers are unionized and may not show any compared with control matrices. Gel layer thickness
interaction [31]. However, further studies are required of XG matrices was 3.8F0.24 mm, while it was just
to confirm this type of interactions for OXB. 2.24F0.33 mm for XG matrices containing fumaric
Presence of fumaric acid in HPMC matrices acid. From the results, it is also obvious that the gel
showed a change in overall gel layer thickness and layer thickness showed no growth with time, and
the work done as compared to gel layer behavior of further there was not much change in gel consistency.
matrices without fumaric acid. It is evident that initial Thus, front synchronization seems to be achieved.
gel formation was delayed, and a significant differ- Anionic polymers are unionized in acidic pH and
ence in gel layer thickness and work done was show less solubility. It can be concluded that presence
observed till 1.5 h. The probable reason could be of fumaric acid created acidic micro-environmental
due to fast release of drug from the surface because of pH in the matrices leading to low polymer solubility
its high solubility in acidic environment created by and enhanced erosion process.
fumaric acid. Initial fast release of drug and excipients Drug release is controlled by the volume
drives the medium into matrix, and increases the water fractions (concentration) of water, polymer and the
 M.V.S. Varma et al. / Journal of Controlled Release 103 (2005) 499–510
drug across the gel layer formed. Due to the pH-
dependent solubility, concentration gradient across
the gel layer will vary as a function of medium pH.
When dynamic swelling/dissolution conditions are
established in a swellable/hydrophilic matrix, a drug
volume fraction gradient is established in the region
between the swelling and erosion fronts. As the
drug starts dissolving at the swelling front, volume
fraction at diffusion front V ds , is given by
V ds=C sd V w/q d, where, C s is solubility (g cm3);
V w, water volume fraction (cm3 water cm3 gel);
q d, drug density [9,28].
It must be noted that for a non-ionizable drug, C s is
independent of medium pH and thus only V w can
change as a function of time. However, for ionizable
drugs C s is highly dependent on pH that exist in the
gel layer and thus both C s and V w factors vary as the
matrix system progress from stomach through intes-
tine, increasing the complexity of drug release
process. Basic drugs like OXB, and other weak bases
with pK a 5–7 show exponential change in the C s as a
function of pH with negligible solubility above pK a,
ultimately changing the diffusion front position and
the V ds.
HPMC matrices gel layer characteristics and
viscosity are pH independent, and thus the gel layer
dynamics should remain constant as the formulation
progress in GIT. However, for basic drugs as the C s is
high at lower pH, drug releases fast from the immature
gel layer at low pH range, which further leads to either
surface erosion of the matrix or increased V w at the
swelling front. Diffusion front position changes in
different pH, thus keeping the micro-environmental
pH constant throughout the release and producing
medium independent drug release. Our data also
indicated that CP and XG polymers which showed
pH-dependent viscosity and gel layer behavior, shows
a sudden release of drugs in lower pH or in the
presence of organic acids. It can be concluded that CP
and XG show pH-dependent drug release for not only
protic molecules but also non-ionic drugs. This
provokes the concept that incorporation of basic
excipients into matrices will not only keep the
solubility of the highly soluble basic drugs low in
the low pH range and thus provide prolonged drug
release without burst effect but will also improve the
gel layer consistency of anionic polymers, irrespective
of the medium.
509
4. Conclusions
This study has demonstrated the influence of pH on
the gel layer behavior and the drug release character-
istics of non-ionic and anionic hydrophilic/swellable
matrices. Addition of 10%w/w fumaric acid to matrices
of various polymers showed pH-independent drug
release. However, most efficient and pH-independent
release was shown only by HPMC polymer matrices,
especially HPMC K15M (50%w/w). Through this
approach, it was possible to design a pH-independent
directly compressible monolithic system for OXB.
Viscosity and texture profiling studies correlated well
with the gel layer behavior under different dissolution
conditions, and to the OXB release from both the non-
ionic and anionic polymer matrices.
Acknowledgements
The authors would like to thank Unichem Lab.
(Mumbai, India) for kindly supplying Oxybutynin
hydrochloride. The authors also wish to thank Mr.
Gunjan for his skillful technical assistance in viscosity
and texture profiling studies, and Mr. Sateesh Kandi-
villi for valuable comments and inputs in mathemat-
ical modeling.
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