Rheology, carbopol

1. 593
Introduction
Among the several routes available for the delivery of
drugs, nasal route has attracted most of the formulation
scientists owing to its advantages such as prevention
of hepatic first pass metabolism and gastrointestinal
(GI) degradation, higher bioavailability at lower dose,
non-invasive, easy for administration, lower risk of
overdose, direct transport into systemic circulation and
targeted brain delivery1
. However, mucocillary clear-
ance is a primary barrier for delivery of drugs, proteins
and peptides by this route. The possible solution for this
problem is prolongation of residence time of drug in the
nasal cavity. Several mucoadhesive polymers such as
chitosan2,3
, carbopol4
, methylcellulose5
, hydroxypropyl
methylcellulose6
, polyvinylacetal diethylaminoacetate7
,
and ethyl(hydroxyethyl) cellulose8
formulated as gels are
extensively reported for prolongation of the residence
time.
Carbopol has been extensively used for preparing
nasal gels9–11
. The widespread use of carbopol for
gel preparation has been attributed to its properties
like good aqueous solubility, gel formation at low
concentration, good bioadhesivity, and compatibility
with many active components, stability and excellent
organoleptic characteristics12
. Carbopols belong to
the class of synthetic high-molecular-weight polymers
of acrylic acid that are crosslinked with either allyl
sucrose or allyl ethers of pentaerythritol. They contain
between 52 and 68% of carboxylic acid (COOH) groups
calculated on the dry basis13
. In solid state, the carbopol
RESEARCH ARTICLE
Rheological investigation and its correlation with
permeability coefficient of drug loaded carbopol gel:
influence of absorption enhancers
Prashant B. Pisal, Sharvil S. Patil, and Varsha B. Pokharkar
Department of Pharmaceutics, Bharati Vidyapeeth University, Poona College of Pharmacy, Erandwane, Pune,
Maharashtra, India
Abstract
Context: The present study was planned to investigate the effect of absorption enhancers on the microstructure of
Losartan potassium gel and hence its influence on the diffusion of Losartan potassium across nasal mucosa.
Method: Losartan potassium loaded carbopol gel (1% w/v) with and without absorption enhancers was prepared.
Polyethylene glycol (PEG) 4000 and ethanol were used as absorption enhancers. Microstructural elucidation of
prepared gels was done using shear rheology. Ex vivo drug release studies were performed on the prepared gels.
Results: It was observed that the absorption enhancers PEG 4000 and ethanol altered the gel microstructure. The
prepared gels were viscoelastic in nature suggesting their suitability for topical application. Permeability coefficient
of Losartan potassium loaded into gels was found to be inversely proportional to the storage modulus. Thus increase
in storage modulus lead to slow drug diffusion.
Conclusion: The current study emphasizes on the fact that selection of polymeric carrier for nasal drug delivery and/
or absorption enhancer strongly influence the microstructure of the gel and hence the pharmaceutical performance
of the formulation.
Keywords: Rheology, storage modulus, Losartan potassium, permeability coefficient, gel microstructure,
absorption enhancers
Address for Correspondence: Prof. Varsha B. Pokharkar, Department of Pharmaceutics, Bharati Vidyapeeth University, Poona College of
Pharmacy, Erandwane, Pune-411038, Maharashtra, India. Tel: +91 20 25437237, Fax: +91 20 25439383, E-mail: vbpokharkar@yahoo.co.in
(Received 06 December 2011; revised 23 April 2012; accepted 04 May 2012)
Drug Development and Industrial Pharmacy, 2013; 39(4): 593–599
© 2013 Informa Healthcare USA, Inc.
ISSN 0363-9045 print/ISSN 1520-5762 online
DOI: 10.3109/03639045.2012.692377
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2. 594 P. B. Pisal et al.
Drug Development and Industrial Pharmacy
molecule often exists as a strongly coiled spiral form.
The unwinding of this spiral structure upon hydration
leads to increase in viscosity. The complete unwinding
of the molecule often ensures the maximum viscosity.
The unwinding of the carbopol resin may be explained
by one of the mechanisms as described below. The most
common mechanism is based on use of appropriate base
for neutralization of the polymer. This neutralization
imposes ionization of polymer leading to generation of
negative charge on the polymer chains. Unfolding of the
structure thus occurs through repulsion between these
charges that on intertwining forms a three-dimensional
matrix resulting in instantaneous formation of a highly
viscous gel14–16
. The second mechanism consists of
hydrogen bond formation induced by addition of a
hydroxyl donor structure to the resin. This process leads
to formation of gel even at acidic pH, however, maximum
thickening may be achieved after several hours. Polyols
such as polyethylene glycol, glycerin and propylene
glycol or non-ionic surfactants containing five or more
ethoxy groups can be used as hydroxyl donors17
.
Losartan potassium (LK), an angiotensin II receptor
antagonist, used for the treatment of hypertension was
selected as a model drug molecule. LK often presents a
problem of low oral bioavailability of around 30% due
to extensive first pass metabolism18
along with gastro-
intestinal disorders, neutropenia, acute hepatotoxicity,
migraine and pancreatitis19
. Moreover, it has a short half
life of about 1.5–2.5 h and its metabolite, (2-n-butyl-4-
chloro-1-[(2’-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]
imidazole-5-carboxylic acid which is more potent has
extended half-life of 3–9 h. Thus it is suitable candidate
for delivery by nasal route20
.
Earlier studies have reported low flux value for LK
being a peptide like molecule21
. There are reports stat-
ing use of absorption enhancers for increasing the flux
of poorly permeable molecules22–24
. In the current study,
we have explored the use of polyethylene glycol 4000 and
ethanol as absorption enhancers. The primary objective
of the study was to investigate rheological properties
of LK loaded carbopol gel with or without absorption
enhancers and its influence on the permeability of LK
across goat nasal mucosa. The microstructure of the gel is
believed to influence the permeability, duration of effect
and absorbability, thus has pronounced effect on overall
therapeutic performance. To understand the influence of
gel microstructure on pharmaceutical performance of the
prepared gel rheological investigation and ex vivo drug
release studies have been performed in the present work.
Materials and methods
Losartan Potassium was generous gift by Torrent
Pharmaceuticals, Gujarat India. Carbopol 934 was pur-
chased from Loba Chemie, Mumbai, India. Ethanol was
purchased from Merck, Mumbai, India. Polyethylene
Glycol 4000 was purchased from SD Fine chemicals,
Mumbai, India.
Gel preparation
An accurately weighed carbopol required for prepar-
ing 1.0% w/v carbopol gel was dispersed in water. The
dispersion was homogenized using an Ultraturrax T25
for 5 min at 8000 rpm, degassed under vacuum and
kept overnight for 8–10 hours. pH of the dispersion was
adjusted to 5.5–6.8 using triethanolamine (10% w/v) to
obtain blank carbopol gel (BG). LK solution (10 mg/mL)
instead of water was used for preparation of LK loaded
gel (LG) keeping the method of preparation same as
described previously. Absorption enhancers i.e. PEG
4000 (0.5% w/v) and ethanol (EtOH, 0.5% w/v) were dis-
solved in LK solution (10 mg/mL). The final solution thus
obtained was used for preparation of LK loaded carbo-
pol gels containing EtOH (LEG) and PEG 4000 (LPG).
Drug content
One gram of LG, LPG and LEG was dissolved separately
in distilled water and volume was made upto 100 mL
in volumetric flask. Absorbance of the solutions was
recorded at 224 nm after filtration to estimate the LK con-
tent. Similar dilutions were prepared for BG and screened
for absorbance if any from the gel constituents. Dilution
of BG did not show any absorbance at 224 nm confirm-
ing the absence of interference by the other excipients
present within the gel. The analysis was performed in
triplicate.
Rheological characterization25,26
Rheological characterization was performed on rheom-
eter (Stress-Tech, Reologica, Sweden) equipped with
cone-plate geometry with cone angle 2°, gap of 0.2 µm
and operating in the oscillation mode. Following tests
were carried out on the prepared gels. All the tests were
performed in triplicate.
Oscillation stress sweep
BG sample was subjected to increasing stress (1–100 Pa)
at a constant frequency i.e. 1 Hz at 25 and 37°C. Similar
procedure was followed for analyzing LG, LPG and LEG.
This test allows determination of the linear viscoelastic
region (LVR) of the sample, and therefore the consequent
choice of the stress value to use in the subsequent oscil-
lation tests.
Frequency sweep
All the prepared samples were subjected to increas-
ing frequency of 1–100 Hz at a constant stress (10 Pa)
obtained from LVR. Effect of stress on elastic modulus
(G′) and viscous modulus (G″) was monitored.
Creep-recovery
In creep recovery, BG sample was subjected to a fixed
stress from LVR i.e. 10 Pa for 100 s and allowed to recover
for 200 s. The creep compliance, J (defined as ratio between
measured strain and applied stress) was recorded against
time. Elasticity of the material in terms of instantaneous
elastic recovery and elastic recovery was determined.
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3. Influence of gel microstructure on permeability coefficient 595
© 2013 Informa Healthcare USA, Inc.
Viscometry test
BG, LG, LPG and LEG were analyzed by viscometry study
wherein stress in the range of 1–100 Pa was applied on
each sample at 25°C.
Ex-vivo drug release studies
Fresh nasal tissues were carefully removed from the
nasal cavity of goat obtained from the local slaughter-
house. Tissue samples were mounted on Franz diffu-
sion cells displaying a permeation area of 3.14 cm2
.
Phosphate buffer saline (30 mL, pH 6.4) was placed in
the acceptor chamber. After a preincubation time of 20
min, LG equivalent to 10 mg of LK was placed in the
donor chamber. At predetermined time intervals, 3-mL
sample was withdrawn from the acceptor compartment.
Sink condition was maintained during the study for a
period of 2 h. Samples withdrawn during the study were
scanned for absorbance using a UV–visible spectropho-
tometer at 224 nm. The amount of LK permeated across
the nasal membrane was estimated. The mechanism
of drug release was estimated by fitting the dissolution
data to Korsmeyer–Peppas equation as shown in the
equation below27
.
M
M
kt
t n
∞
=
(1)
Where Mt
represents the fraction of drug released in
time t and M∞
the amount of drug released after infinite
time. The diffusional exponent of drug release ‘n’ indi-
cates the type of release mechanism during the dissolu-
tion process. For non-Fickian release, the n value falls
between 0.5 and 1.0, while for Fickian diffusion, n = 0.5.
k represents a constant incorporating structural and geo-
metrical characteristic of the device.
The effective permeability coefficients (Peff
) (cm·s−1
)
under steady-state conditions across excised mucosa can
be calculated according to Equation 2.
P
dC
dt
V
AC
e
ss
ff
d
=





 ×
(2)
where (dC/dt)SS
(μg·mL−1
·s−1
) is the time-dependent
change of concentration in the steady-state; A (cm2
) is
the permeation area; V (mL) the volume of the receiver
compartment; and Cd
(μg·mL−1
) is the initial donor
concentration28
. The data obtained was analyzed statisti-
cally by using Dunnett Multiple comparison test.
Results and discussion
Based on the preliminary gel screening studies (data not
shown), 0.5% w/v was the selected concentration of the
absorption enhancer.
Since the primary objective of the work was to eluci-
date microstructure of gel after addition of enhancers
and its correlation with permeability coefficient of LK,
the amount of absorption enhancer was kept constant.
Drug content
Losartan potassium (LK) within the prepared gels was
found in the range of 98.74–99.23 %w/w which may be
attributed to free solubility of Losartan potassium in
water leading to uniform distribution of drug within gel
and thus ensuring minimal drug loss during gel prepara-
tion process. Moreover there was non significant change
in drug content values when determined at different time
intervals for three months suggesting stability of drug
within the prepared gels.
Rheological characterization
It is very well reported that the rheological analyses
provide information regarding the microstructure of the
sample under consideration29
. The primary step towards
understanding of microstructure of sample using rhe-
ology is often associated with determination of linear
viscoelastic region (LVR). The LVR was obtained by per-
forming the oscillation stress sweep.
Oscillation stress sweep
In oscillation stress sweep a series of amplitudes are
given and phase length (frequency) is kept constant. In
this dynamic test, the elastic modulus G′ is measured as
a function of stress at a constant frequency. The range of
stress over which G′ is independent of the applied stress
amplitude is called the LVR. The LVR presents a critical
stress beyond which the sample may show significant
structural breakdown. The mean stress value obtained
from LVR was used for other oscillation tests such as
frequency sweep and creep recovery. Thus LVR indicates
ability of the sample to retain its microstructure when
Table 1. Summary of rheological parameters and flux values for Losartan potassium (LK) in the prepared gels.
Formulation
Rheological parameters
Flux (J)
10−3
mg/cm2
G′ Pa (100 Pa) at 25ºC G′ Pa (100 Pa) at 37ºC LVR Pa
Percent creep
recovery
BG 329.55 ± 9.93 647.31 ± 10.23 1–16.8 87.25 ± 3.03 –
LG 408.85 ± 8.36** 728.43 ± 8.75** 1–20.2 94.04 ± 2* 5.22 ± 0.11
LEG 247.82 ± 10.22** 539.23 ± 7.47** 1–13.9 72.64 ± 2.86** 5.7 ± 0.13**
LPG 280.89 ± 8.195** 597.52 ± 5.94** 1–18.4 81.01 ± 2.23* 5.1 ± 0.14
Mean ± SD, n = 3, Dunnett multiple comparison test.
BG, blank carbopol gel; LG, LK loaded carbopol gel; LEG, LK loaded carbopol gel containing EtOH; LPG, LK loaded carbopol gel
containing PEG 4000.
*p 0.05, **p 0.01.
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4. 596 P. B. Pisal et al.
Drug Development and Industrial Pharmacy
perturbed by the shearing stress. In other words, higher
the LVR higher will be the microstructural stability of
the sample under the influence of oscillatory shearing
stress30
. Table 1 shows LVR for the prepared gels.
Figure 1 clearly shows the LVR for blank gel (BG) and
LK loaded carbopol gel (LG) is comparable indicating
that the addition of drug did not alter the microstructural
stability of the gel. However the addition of ethanol in LG
(LEG) reduced LVR drastically when compared to LG.
G′ is a measure of energy stored and recovered per
cycle of deformation and reflects the solid like component
of the viscoelastic material. G′ will be large if a material is
predominantly elastic or highly structured. The addition of
drug showed drastic increase in G′ when compared to BG,
whereas addition of absorption enhancers in LG reduced
G′. The order of increment in G′ was LG BG LPG LEG.
This dramatic rise in the G′ of LG may be attributed to
the potassium ion present in gel which has basic character.
The localized increase in pH and subsequent neutraliza-
tionofthepolymermoleculemighthaveinducedcomplete
unwinding of polymer chains that increased repulsion
between like negative charges. Such repulsion might have
generated more closely packed network of polymer chains
leading to increment in storage modulus (G′). Yet another
reason for such increase in elastic nature within gel is the
salting out or chaotropic effect of potassium ion, which
is known to break the tetrahedral structure of water mol-
ecules thus preventing hydration of the polymer chains31
.
However, addition of polyol i.e. PEG 4000 in LG (LPG) did
not increase LVR and G′ as compared to LG. This may be
attributed to the salting out activity of potassium ions
whichhavebeenreportedtothehinderthehydrogenbond
formationprocessbetweenpolymerchainsandwatermol-
ecules. LEG showed lowest LVR and G′ when compared to
other gels. It is very well proven that ethanol is acidic in
nature. Thus addition of ethanol creates acidic microenvi-
ronment which might have prevented swelling of polymer
microstructure ultimately reducing LVR and G′. This was
further investigated using frequency sweep test.
Frequency sweep
To obtain information about viscoelastic behavior of
the prepared systems oscillation frequency sweep test
was conducted. An oscillation frequency sweep test is
a dynamic test measuring the response of a system as
a function of frequency at constant stress amplitude
(within LVR). Elastic modulus (G′) and viscous modulus
(G″) were determined as a function of frequency. G″ is
a measure of the energy lost per cycle and reflects the
fluid-like component. G″ will be large when the sample is
predominantly viscous. A frequency sweep test provides
fingerprint of a viscoelastic system under non-destruc-
tive conditions when performed within the LVR32,33
. Thus,
systems were examined in their rheological ground state
without disrupting the structure.
The rheological data obtained from oscillatory fre-
quency sweep test was analyzed using power law model.
The slope ‘s’ of log G′ versus log Frequency curves was
determined which represents the degree of structuring in
the gel systems. A lower s value indicates greater degree
of structuring in the gel34
. The addition of LK to blank gel
(s = 0.3018) increased the s value of LG (s = 0.4314) indicat-
ing reduction in the degree of structuring in the gel sys-
tem. Such alteration in the degree of gel structure may be
attributed to the salting out effect due to potassium ions.
The addition of ethanol to LG showed increment in s value
suggesting more alteration in gel structure by the ethanol
molecules. However, addition of PEG 4000 dramatically
reduced the s value close to BG. The polyethylene chains
associated with PEG might have contributed to higher
structuringofthegelthroughinteractionwiththecarbopol
polymer chains. The reason behind this may be attributed
to the hindrance induced by potassium ion to the hydro-
gen bond formation between polymer chains and water
molecules keeping their elastic nature intact. Moreover,
all the prepared gels showed viscoelastic nature when per-
turbed by oscillatory frequency (Figure 2). However, the
elastic nature was found to be predominant in all the gels.
The elastic nature associated with the prepared gel was
further confirmed using creep recovery test.
Creep-recovery
In creep test a constant stress within LVR is applied for
a fixed time (100 s) and then removed (200 s). The test
depicts percentage of elastic character present within
system (Figure 3).
Figure 1. Plot of oscillation stress sweep study for the prepared gels. Figure 2. Plot of frequency sweep study for the prepared gels.
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5. Influence of gel microstructure on permeability coefficient 597
© 2013 Informa Healthcare USA, Inc.
Percent creep recovery was calculated by using the
formula given below.
δJ
J s J s
J s
=
−
×
( ) ( )
( )
100 300
100
100






(3)
Table 1 shows percent creep recovery data for the
prepared gels. The higher the value of creep recovery, the
more will the elastic component be present within the
system.Resultsofcreeptestwereinagreementwithstress
sweep studies. The addition of LK to blank Carbopol gel
showed significant increase in creep recovery suggesting
increase in elastic component (p 0.01). Such increase in
elastic component may be attributed to the salting out or
chaotropic effect of potassium as explained previously.
The addition of PEG and ethanol significantly reduced
percent creep recovery suggesting reduction in elastic
component (p 0.01). Thus addition of PEG and etha-
nol rendered viscous nature to the system. Gels when
applied topically should exhibit viscoelastic character for
effective spreading on the skin surface35
. Thus absorption
enhancers such as ethanol and PEG used for preparing
LK gels also effectively introduced viscous component
within gels which may contribute to the effective spread-
ing of gel on skin surface.
Viscometry
The viscosity of prepared gels was investigated through
viscometry studies and the viscometry data was analyzed
by Power law model as depicted below.
Stress = Consistency co-efficient × (Shear rate)n
(4)
Power law index (n) suggests flow behavior of the
samples. If n 1 the material is shear thinning whereas
n 1 represents shear thickening material. The correla-
tion coefficient for the above model was found to be
above 0.9 suggesting its suitability for extracting the rheo-
logical parameters for the viscometry data generated. The
values of n observed in the present study were well below
1 (Table 2), indicating that the prepared gels were shear
thinning. The shear thinning behavior associated with
the prepared gels may be attributed to the elongation
of polymer random coils under the influence of shear36
.
The yield stress, minimum force required for the mate-
rial to behave as Newtonian fluid was also determined
(Table 2). The results of yield stress were in agreement
with stress sweep and creep recovery studies. LG showed
significantly higher value for yield stress (p 0.01) sug-
gesting that more force would be required for making it
Newtonian. It was obvious since LG presented more elas-
tic component that might have prevented energy dissipa-
tion introduced through shear stress. Addition of ethanol
and PEG reduced yield stress significantly indicating
increase in viscous component within the gel, reason for
which has been discussed previously. The effect of addi-
tion of absorption enhancers on release kinetics was also
investigated.
Ex-vivo drug release studies
Carbopol has been well reported to open the tight cellular
junctions when in contact with the epithelial lining and
hencewasselectedforformulatingnasalgelofLK37,38
.Drug
release was plotted as cumulative percent drug release
versus time (Figure 4). The values of n extracted by fitting
the dissolution data to Korsmeyer–Peppas equation lied
between 0.7 and 1.0 for all drug loaded gels indicating that
thedrugreleasewasfollowingnon-Fickianreleasekinetics.
Thus drug-release mechanisms involve a combination of
diffusion and polymer chain-relaxation mechanisms39
.
The amount of drug released after 1 h (t60
) was estimated.
It was observed that addition of ethanol to LG significantly
increased the percent drug release after 1 h (76.77 ± 1.55
%, p 0.05) when compared to LK gel without absorption
enhancer (72.87 ± 1.4%). However, addition of PEG did not
affectthedrugreleaseofLK(72.30±1.8%)incaseofLPG.The
gel consistency loss occurring in LPG due to PEG induced
carbopol desolvation and precipitation after salification
of the carboxylic groups might have been responsible for
slow drug release40
. The flux values for all the samples
were determined after 90 min as depicted in Table 1. LEG
had significantly high flux value among all the prepared
samples (p 0.01). There was no significant change in the
flux values of LK for LPG and LG. The influence of change
in microstructure of LK gel after addition of absorption
enhancersandhenceondiffusioncharacteristicsofLKcan
be depicted if one generates correlation amongst two. For
Figure 3. Plot of creep recovery study for the prepared gels.
Table 2. Summary of viscometry study performed on blank and
Losartan potassium (LK) loaded gels.
Formulation
Power law
index (n) Yield stress, (Pa) Behaviour
BG 0.398 31.62 ± 2.84 Shear thinning
LG 0.213 40.21 ± 2.09* Shear thinning
LEG 0.628 13.59 ± 2.16** Shear thinning
LPG 0.532 23.20 ± 1.95* Shear thinning
Mean ± SD, n = 3, Dunnett multiple comparison test.
BG, blank carbopol gel; LG, LK loaded carbopol gel; LEG, LK
loaded carbopol gel containing EtOH; LPG, LK loaded carbopol
gel containing PEG 4000.
*p 0.05, **p 0.01.
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6. 598 P. B. Pisal et al.
Drug Development and Industrial Pharmacy
the same purpose G′ values at 37°C for prepared gels
were determined so as to have a better correlation with
the drug release. The G′ values determined at 37°C were
found to be considerably higher for all the prepared
gels when compared to those observed at 25°C
(Table 1). Such drastic increase in G′ values at 37°C may
be attributed to the thermally induced dehydration
of polymer chains which might have increased their
mobility41
. This higher mobility resulted in increased
drug permeability at 37°C. The addition of absorption
enhancers reduced storage modulus of LG and in turn
increased the permeability coefficient. It was observed
that changes in storage modulus and permeability
coefficient could be best described by an exponential
function (Figure 5). Moreover, the slope of trend line
for storage modulus was found to be positive (0.1503)
whereas that for permeability coefficient was negative
(−0.0595), thus confirming the inverse relationship
between storage modulus and permeability coefficient.
The reason behind such relationship may be attributed
to increase in fluid like component within the system
that helps in the faster movement of LK through the
gel, which in turn increased the percentage LK release
from the prepared gels.
Conclusion
In the present work influence of microstructural changes
as revealed by rheology on permeability coefficient has
been investigated. It was observed that storage modulus
of the prepared gel is inversely proportional to the perme-
ability coefficient of LK. Further ethanol was found to be
suitable absorption enhancer for the prepared Losartan
potassium gel when compared to PEG 4000. The current
study emphasizes on the fact that selection of polymeric
carrier for nasal drug delivery and/or absorption enhancer
strongly influence the microstructure of the gel and thus
the pharmaceutical performance of the formulation.
Declaration of interest
The authors report no conflicts of interest. The authors
alone are responsible for the content and writing of this
paper.
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Figure 5. Correlation between storage modulus (determined at
37°C) and permeability coefficient of Losartan potassium (LK)
from prepared gels.
Figure 4. Ex vivo drug release studies for the prepared gels.
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7. Influence of gel microstructure on permeability coefficient 599
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