European Journal of Pharmaceutical Sciences 20 (2003) 429–438

Interactions of ibuprofen with cationic polysaccharides

in aqueous dispersions and hydrogels
Rheological and diffusional implications
Rosal´ıa Rodr´ıguez, Carmen Alvarez-Lorenzo∗ , Angel Concheiro
Departamento de Farmacia y Tecnolog´ıa Farmacéutica, Facultad de Farmacia, Universidad de Santiago de Compostela,
Santiago de Compostela 15782, Spain
Received 8 July 2003; received in revised form 11 September 2003; accepted 11 September 2003

Abstract

Non-steroidal antiinflammatory drugs, such as ibuprofen, are amphiphilic substances capable of self-association in aqueous solutions and
able to be sorbed onto polymers through hydrophobic and electrostatic bonds. The aim of this work was to analyze the association processes
of sodium ibuprofen with cationic celluloses (Celquat® H-100 (PQ-4) and SC-230M (PQ-10)) and cationic guar gums (Ecopol® 261-S and
14-S) and their repercussions on the properties of the aqueous dispersions and cross-linked hydrogels. The interaction process was studied
in aqueous dispersions through transmittance, surface tension, fluorescence, conductivity, viscosity and oscillatory rheometry measurements.
Below cmc, the drug molecules weakly interact with the polymers through hydrophobic and ionic interactions. Around the cmc (4%), a
notable decrease in the viscosity, and storage and loss moduli of the dispersions (even precipitation in PQ-10 systems) was observed. An
additional increase in drug concentration induced the dispersions to recover their initial properties. Since ibuprofen/polymer cationic groups
ratio were in all cases above 1, these observations indicate that drug self-association induces the polymer to coil around the micelles and, as
the number of micelles increases (more drug concentration) the polymer chains interact with more of them, un- coiling again to some extent.
Polymer (1%) dispersions containing 6% ibuprofen showed drug diffusion coefficients much lower than in water. When a surfactant, sodium
dodecylsulfate, was added to these systems the diffusion coefficients decreased even more, suggesting the formation of new associative
structures. Chemically cross-linked hydrogels made of these cationic polysaccharides absorb consid- erable amounts of ibuprofen (up to 15
g/g) and showed a pH-dependent release process. At acidic pH, drug–polymer affinity is main- tained, preventing drug release. In contrast,
at pH 8 the interactions are broken and the release process is sustained for more than 4 h. In summary, ibuprofen interactions with
cationic polysaccharides strongly determine the performance of their aqueous dispersions and hydrogels.
© 2003 Elsevier B.V. All rights reserved.

Keywords: Amphiphilic drugs; Cationic cellulose; Cationic guar gum; Sodium dodecyl sulfate; Polymer–surfactant interactions

1. Introduction (Pouliquen et al., 2003). Most semi-synthetic polysaccha-

Polymer association with complementary additives that
can rapidly strengthen or induce connections between the
polymeric chains has been shown as a useful way to obtain
considerable increases in the viscosity of the dispersions—
avoiding the difficult handling of high concentrations or
high molecular weight polymers—or even the creation of
responsive systems whose properties are modulated by
changes of the affinity between the polymer and the additives
∗
+
Corresponding author. Fax: 34-981-547148.
E-mail address: ffrusdog@usc.es (C. Alvarez-Lorenzo).
rides have a particularly adequate structure to interact with
amphiphilic molecules, which is interesting for this type of
applications. Cellulose and guar gum derivatives present a
glucosidic backbone that may establish hydrophobic inter-
actions, while the presence of hydrophilic or charged groups
in their substituents provides the polymer with hydrogen
bonding capacity or high affinity for oppositely charged
molecules. In several papers, the use of surfactants to in-
duce changes in the conformation of cationic polysaccha-
rides and to promote the formation of aggregates has been
proposed as a way to obtain homogeneous aqueous disper-
sions and to modulate their rheological behavior (Goddard

0928-0987/$ – see front matter © 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.ejps.2003.09.004
430 R. Rodr´ıguez et al. / European Journal of Pharmaceutical Sciences 20 (2003) 429–438
and Hannan, 1977; Hoffman et al., 1996; Chronakis and
Alexandridis, 2001). Additionally, the high bioadhesive ca-
pacity (Gruber and Kreeger, 1996) and low toxicity (Annon,
1988) of hydrophilic cationic polysaccharides make them
particularly useful for preparing cosmetic preparations and
drug delivery systems able to combine long residence times
at the application site with adequate mechanical properties.
As classical surfactants, many kinds of drugs—i.e., tri-
cyclic antidepressants, þ-blockers, phenotiazine tranquiliz-
ers, antihistamines, non-steroidal antiinflammatory drugs
(NSAIDs) and local anesthetics—are surface-active sub-
stances capable of self-association in aqueous solutions
(Florence and Attwood, 1998; Taboada et al., 2001) and able
to be sorbed onto polymers through hydrophobic and elec-
trostatic bonds (Hugerth, 2001; Mura et al., 2003; Yomota
and Okada, 2003). The repercussions of these phenomena
on the properties of polymer gels depend on the tendency
of the drug to aggregate and on the strength of its interac-
tions with the polymer (Alvarez-Lorenzo and Concheiro,
2003). In Carbopol® 1342 gels, alprenolol forms, at low
drug concentrations, micelle-like aggregates with the poly-
mer lipophilic residues, increasing the elastic and viscous
moduli of the gels. However, as the drug concentration is
raised, the consistency decreases, the gel collapses and,
when alprenolol amino groups neutralize the carboxylic acid
groups of the acrylic polymer, precipitation occurs
(Paulsson and Edsman, 2002). The changes observed in
alprenolol diffusion rate are a consequence of both the
interactions with the polymer and the changes induced in
the viscosity of the systems. Interaction of phenothiazines
(chlorpromazine, trifluoromazine, promazine, and promet-
hazine) with hyaluronate causes the gels made of this an-
ionic polymer to shrink; the minimum drug concentration
required for that being proportional to the critical micellar
concentration, cmc (Yomota and Okada, 2003). The po-
tential as periodontal drug delivery systems of non-ionic
cellulose ether–surface-active anesthetic drug gels was high-
lighted by Scherlund et al. (2000). Lidocaine and prilocaine
do not interact with ethylhydroxyethyl cellulose (EHEC) or
hydrophobically modified EHEC (HM-EHEC) but strongly
affect their interactions with sodium dodecylsulfate and
myristoylcholine bromide. In consequence, the drug loaded
systems notably differed from polymer–surfactant disper-
sions in the storage and loss moduli.
Non-steroidal antiinflammatory drugs (NSAIDs), such as
sodium ibuprofen, adsorb onto the non-ionic cellulose ethers
non-cooperatively up to the cmc and cooperatively above
this concentration (Ridell et al., 1999). Near cmc, ibupro- fen
causes phase separation of EHEC dispersions, because of a
strong hydrophobic interaction that shrinks the polymer
chains but, above cmc, micelles of ibuprofen solubilize the
hydrophobic parts of the polymer. The presence of apolar re-
gions and ammonium groups in the cationic polysaccharides
could enhance the intensity of interactions with the aromatic
ring and the hydrophilic carboxylic group of NSAIDs, mak-
ing it possible to combine both hydrophobic association and
Coulombic forces. These interactions may induce changes in
the system which can be foreseen as useful to achieve an effi-
cient control of the release process from aqueous dispersions
(Paulsson and Edsman, 2001; Jimenez-Kairuz et al., 2002)
or chemically cross-linked hydrogels (González-Rodr´ıguez
et al., 2002; Rodr´ıguez et al., 2003a).
The aim of this work was to analyze the association pro-
cesses of sodium ibuprofen with cationic celluloses and
cationic guar gums and their repercussions on the properties
of the aqueous dispersions and cross-linked hydrogels. Two
varieties of cationic hydroxyethyl celluloses and two vari-
eties of cationic guar gums, differing in molecular weight
and content and distribution of the cationic groups, were
used to evaluate the influence of polymer molecular struc-
ture. Additionally, the effect of the concomitant presence of
an anionic surfactant, sodium dodecylsulfate, which may
compete with the drug for the binding to the polymer, was
considered. Since NSAIDs are suitable candidates for incor-
poration into polymer dispersions (physical gels) for topical
application or into hydrogels that release them at the small
intestine, minimizing the adverse gastric drug effects after
oral administration (Dominkus et al., 1996), a preliminary
evaluation of the potential interest of the dispersions and
hydrogels as drug delivery systems was also carried out.
2. Materials and methods
2.1. Materials
Polyquaternium-4 (PQ-4) (Celquat® H-100, batch FGS
1014) and Polyquaternium-10 (PQ-10) (Celquat® SC-230
M, batch GFS 1139) were provided by Na- tional Starch
and Chemical Ltd., UK. Ecopol® 261-S (E-261, batch
L10159215) and Ecopol® 14-S (E-14, batch L10159214)
were from Economy Polymers & Chemi- cals, USA.
Sodium ibuprofen, sodium dodecylsulfate and
ethyleneglycol diglycidylether (EGDE, 50 vol.% in water)
were from Sigma–Aldrich Chemical Co., USA. Purified
water by reverse osmosis (MilliQ®, Millipore Spain) with
resistivity >1.82 MK cm was used. All other reactives were
of analytical grade.
2.2. Methods
2.2.1. Preparation of the dispersions
Aqueous dispersions containing 1.0% (w/w) cationic cel-
lulose and a wide range of ibuprofen concentrations (0–8%,
w/w) were prepared by dispersing the required amounts of
each component in 100 ml of water under stirring. The sys-
tems were left to stand for 24 h before characterization. All
studies were carried out at 25 ◦C.
2.2.2. Cloudiness
The cloudiness of dispersions was determined by mea-
suring transmittance at 800 nm (Shimadzu UV-240, Japan)
against a blank of cationic polysaccharide dispersion.
 R. Rodr´ıguez et al. / European Journal of Pharmaceutical Sciences 20 (2003) 429–438
2.2.3. pH
The measurements were made with a pH-meter Crison,
model GLP22 (Spain), equipped with a sensor (Ag/AgCl)
for viscous media no. 52-21.
2.2.4. Conductivity
Conductance measurements were made in a rhadiometer
conductivity meter model CDM2e (Denmark) equipped with
a Crison platinum sensor (Spain).
2.2.5. Surface tension
The measurements were made using the platinum ring
method with a Lauda tensiometer TD1 (Germany) applying
the necessary density corrections.
2.2.6. Steady-state fluorescence measurements
Pyrene (Py) emission spectra (λ=350–450 nm) were
recorded in a Perkin-Elmer LS50B fluorescence spectropho-
tometer (UK), with the excitation wavelength set to 310 nm
and slits set to 5 and 5, for excitation and emission, respec-
tively. The samples were prepared by the addition of polymer
(0.5% cationic celluloses or 0.1% cationic guar gums) and
ibuprofen (0.5–7%) to a pyrene aqueous solution (10−6 M)
and stored at 25 ◦C for 24 h. The ratio of the intensity at the
first (I1 at 373 nm) and the third (I3 at 392 nm) vibronic peaks
was used as an index of the local hydrophobicity of the
polymer–surfactant aggregates (Rodr´ıguez et al., 2003b).
2.2.7. Viscosity
Determinations of apparent and specific viscosity were
carried out in Cannon-Fenske capillary viscometers (Afora,
Spain).
2.2.8. Viscoelastic behavior
The rheological behavior of the polymer dispersions with
and without ibuprofen was evaluated, in triplicate, in a Rheo-
lyst AR-1000N rheometer (TA Instruments, UK) equipped
with an AR2500 data analyzer, fitted with a Peltier temper-
ature control, and a 6 cm cone-plate measuring geometry,
covered with a solvent trap. Oscillatory shear responses (G±
or storage modulus, and G±± or loss modulus) were deter-
mined at 0.1 Pa over the frequency range of 0.01–50 rad s−1.
The test conditions were inside the linearity range of the
viscoelastic properties.
2.2.9. Ibuprofen diffusion assays
Drug release profiles from 1% polymer dispersions con-
taining 6% ibuprofen (and in some cases SDS at different
concentrations) were obtained in triplicate in Franz-Chien
diffusion cells (Vidra-Foc, Spain), thermostated at 37 ◦C,
and fitted with cellulose acetate filters (0.45µm pore size,
Teknokroma, Spain) after previous storage at the same tem-
perature for at least 1 h. The area available for diffusion was
431
magnetic rod. Samples (0.10 ml) were taken from the recip-
ient compartment at intervals over a 10-h period, for deter-
mination of ibuprofen on the basis of absorption at 273 nm
(Shimadzu UV-240, Kyoto, Japan); in each case, recipient
medium volume was immediately made up with iso-osmotic
solution. Diffusion coefficients were estimated by non-linear
regression applying the Higuchi (1962) equation
1/2
A . π Σ (1)
Q Dt
= 2C0
where Q/A is the amount of ibuprofen released per unit area
at the time t, and C0 is the initial concentration of ibuprofen
in the dispersion.
2.2.10. Hydrogel synthesis
Hydrogels were synthesized as described previously
(Rodr´ıguez et al., 2003a). Briefly, EGDE (2 ml) was added
to a 3% cationic cellulose dispersion in 0.10 M NaOH
medium (10 ml) or to a 2% cationic guar gum solution in
0.05 M KOH medium (10 ml). After stirring for 5 min, the
mixture was transferred to a test tube of 10.5 mm i.d., and
hermetically closed. The tubes were kept at 60 ◦C for 6 h, in
the case of guar gums, and 24 h, in the case of cationic
celluloses. After cooling, the hydrogels were carefully re-
moved and immersed in ultrapure water for 24 h to swell.
The hydrogels were then transferred to HCl 0.1N solution
for 12 h to neutralize the basic medium, and finally kept in
ultrapure water for 1 week, changing the medium every 12 h
to allow a complete wash out of non-reacted substances.
2.2.11. Equilibrium swelling of hydrogels
After being immersed in ibuprofen solutions (as explained
below), equilibrium diameters d of pieces of cylindrical gels
were measured using a digital micrometer. The degree of
swelling was expressed as
3
= V
. Σ
Swelling ratio (2)
V0 = d
d0
where d0 was the diameter of gel discs upon synthesis
(10.5 mm).
The water content of the hydrogel was estimated by the
difference between the weight of fully swollen hydrogel
samples (W), after careful wiping of their surfaces with a soft
tissue, and the weight of the samples after being dried (W0)
for 1 week at 40 ◦C
(W − W0)
Q = (3)
W0
2.2.12. Ibuprofen sodium loading and release from
cross-linked hydrogels
0.785 cm2. A sample of 2.5 ml was placed in the donor com- partment;
while 6.0 ml of iso-osmotic NaCl aqueous solu- tion filled the recipient
 432
compartment R. Rodr´ıguez
and was stirred with a et al. / European Journal of Pharmaceutical
Pieces ofSciences 20 (2003) 429–438
the cylindrical gels (2–3 mm thickness) were
placed in 10 ml aqueous solutions of 1–8% drug for 3 days
at room temperature. The amount loaded was determined as
the difference between the initial amount of drug and the
amount remaining in the outer solution after the 3 days,
 R. Rodr´ıguez et al. / European Journal of Pharmaceutical Sciences 20 (2003) 429–438 433

which was measured spectrophotometrically (λ= 273 nm; PQ-10

Shimadzu UV-240, Japan). Then, each loaded hydrogel was H OH H H
superficially rinsed with water and directly immersed in 50 HO H OH
HO
ml water of pH 3 (HCl aq.), pH 6 (not adjusted), or pH 8 HO
O

(phosphate buffer), and kept at 37 ◦C. The release was also

HO O
H H O
OH Cl-

evaluated when the hydrogels where immersed first in pH H H H O (CH CH O) CH CHOHCH N+(CH )

2 2 n 2 2 3 3
3 medium (for 2 h) then, transfer to pH 6 medium (for 2 h), P Q-4

and subsequently to pH 8 solution. The experiments were

H O (CH2CH2O) nH H H
carried out in triplicate. The amount of ibuprofen released
OH
was measured spectrophotometrically (λ = 273 nm) in pe-
HO H
HO O
HO
HO O

riodically taken samples and again placed in the same ves- OH

H O
sel so that the liquid volume was kept constant. The release
H O ( CH2CH2O) nH
profiles between 10 and 80% were characterized by fitting
the following equation by non-linear regression (Korsmeyer
Cl-
and Peppas, 1981)
Cl-

Mt n
Ibuprofen ONa

= Kt (4)
M∞

where Mt/M ∞ is the fraction of drug released at time t.

E-14 and E-261
To detect the presence of ibuprofen remaining in the hy-
OHO R
drogels after the release tests, IR spectroscopy was used. R = H or CH2CHOHCH2N+(CH3)3Cl- H
HO
Samples of hydrogels used for the loading/release were dried
in an oven at 40 ◦C until constant weight, and powdered in
H
HO
H OH
a mortar. IR spectra were recorded over the range of 400–
H
4000 cm−1, in a Bruker IFS 66 V FT-IR spectrometer H OH HO

(Germany), using the potassium bromide pellet technique. OH O OH O

The characteristic peaks of ibuprofen appear at 2956 cm−1, HO O

HO O
benzene ring, and 1584 and 1409 cm−1, ionized carboxylic H H H H z

H H H H
groups (Higgins et al., 2001).

were, in general, homogeneous. Transmittance was in some cases even

greater than that of the polymer alone dispersions. Precipitation was
3. Results and discussion only observed for the PQ-10 dispersions containing 4–5% ibuprofen
(Fig. 2). The pH of the systems
The structure of the polymers is shown in Fig. 1. PQ-10
and PQ-4 are linear cationic hydroxyethyl celluloses in
which the ammonium groups are bonded to the hydroxy-
ethyl substituent (PQ-10) or directly grafted to the cellulose
backbone while the hydroxyethyl substituent remains un-
altered (PQ-4). On the other hand, cationic guar gums are
formed by mannose units linearly bonded that alternatively
have a lateral ramification of galactopiranose. Some po-
sition 6 hydroxyl groups of galactopiranose are bounded to
a hydroxypropyltrimethylammonium group. In addition to
these general differences, the polymers also differ in
molecular weight and amount of cationic groups as reported
previously (Table 1) (Rodr´ıguez et al., 2001).

3.1. Aqueous dispersions

3.1.1. Study of the interactions in aqueous dispersions

Aqueous dispersions of cationic celluloses and cationic
guar gums prepared with several ibuprofen concentrations
Fig. Rodr´ıguez
434 1. Molecular structures ofR. the et al.celluloses
cationic / European Journal of Pharmaceutical Sciences 20 (2003) 429–438
(polyquaternium-4 and polyquaternium–10), the cationic guar
gums (Ecopol® 261-S and 14-S differ in the content in the
cationic groups), and ibuprofen.

increased linearly from around 7 (for PQ-10 and

PQ-4) or 6 (E-14 and E-261) to 8.5 when
ibuprofen concentration changed from 0 to 8%;
the ibuprofen–cationic polysaccha- ride systems
showing the same pH values as the ibuprofen
sodium solutions. The conductivity of the systems
also in- creased from 650–800 to 10,000–12,000
µS/cm with drug concentration, not showing any
inflection points.
The surface activity of ibuprofen was clearly
seen when the evolution of pyrene fluorescence
and surface tension

Table 1
Molecular weight (MW), intrinsic viscosity in water at 25 ◦C
([η]), and characteristics of substitution of the cationic
celluloses and cationic guar gums (Rodr´ıguez et al., 2001)
Polymer MWa [η] (dl/g) MSHECb %N Ammonium
group/sugar
repeating unit
PQ-4 1400000 14.59 2.71 1.27 1:5.3
PQ-10 1700000 70.09 1.28 1.95 1:2.9
E-14 500000 46.78 – 1.16 1:6.5
E-261 200000 45.85 – 0.91 1:8.5
a Dataprovided by the supplier.
b MSHEC average number of hydroxyethyl substituents =
bonded to each glucopiranose unit.
 R. Rodr´ıguez et al. / European Journal of Pharmaceutical Sciences 20 (2003) 429–438 435

120 1000 70

Surface tension (mN/m)

100 800 60
Transmittance (%)

Viscosity (mPa·s)
80 600 50

60 400
40
40 200
30
20 0 P

210 6000 70
E-261
180

Surface tension (mN/m)

5000 60
Transmittance (%)

Viscosity (mPa·s)
150 4000
50
120 3000

2000 40
90
1000
30
60
0
012345678 012345678 012345678
Ibuprofen (%)

Fig. 2. Transmittance, viscosity and surface tension of aqueous dispersions of cationic polysaccharides (1%) containing different proportions of ibuprofen (P:
precipitation of PQ-10 dispersions).

measurements as a function of drug concentration were
recorded. With both techniques, the cmc obtained for
ibuprofen in water, 4%, was similar to the value found by
Ridell et al. (1999). The minimum observed can be at-
tributed to some surface-active impurities in the drug. The
micropolarity of the medium was measured by the changes
in the I1/I3 ratio in the emission spectra of pyrene. The I1/I3
ratio is higher in a polar medium (1.87 in water) than in an
apolar medium (0.66 in cyclohexane) (Anthony et al., 1998).
Without ibuprofen, cationic polysaccharides showed a I1/I3
ratio around 1.2. In the presence of 5% ibuprofen, this value
decreased to 0.9, in PQ-4 dispersions, and to 0.70–0.75, in
the other cationic polysaccharide systems. The greater I1/I3
ratio of PQ-4/ibuprofen dispersions is ex- plained by the
more hydrophilic character of this polymer, which have
more hydroxyethyl groups. The surface tension of the
ibuprofen–cationic polysaccharide dispersions de- creased,
from 50–60 mN/m, in the presence of the drug to reach a
minimum, 30 mN/m, around 4% ibuprofen (Fig. 2). No
significant differences were observed in the surface ten- sion
patterns with respect to that obtained in the absence of
polymer, which indicates that none of these cationic
polysaccharides significantly interferes in the micellization
process of the drug and that the main interactions may hap-
pen for drug concentrations around or above cmc. These
observations were confirmed by the changes that occurred in
the transmittance and rheological properties of the dis-
persions. The viscosity of the systems containing ibuprofen
at a concentration around cmc was considerably lower than
that of the polymer dispersions in the absence of the drug
(Fig. 2). The effect was less pronounced for PQ-4 systems
that showed, as the E-14 dispersions, a significant increase
in viscosity for lower drug concentrations. In general, the
values of G± and G±± followed a tendency similar to that of
viscosity and continuously decreased until the drug con-
centration reached the cmc (4%). An additional increase in
drug concentration induced the dispersions to recover their
initial properties, showing G± and G±± values similar to or
even greater than those of polymer alone dispersions (Figs.
3 and 4).
These observations may be explained taking into account
the electrostatic and hydrophobic interactions that may be
established between the drug and the polymers. Even for the
lowest drug concentration studied (0.5%), the molar ra- tio
of carboxylic drug groups/ ammonium polymer groups was
greater than 1; this means that in all systems there are
enough ibuprofen molecules to ionically neutralize all
cationic groups of the polymer. Therefore, although be- low
cmc the interaction seems to be scarcely significant, some
drug molecules may act as bridges between different
polymer chains, favoring the formation of a three dimen-
sional network of slightly greater consistency. Considering
the viscosity and transmittance data, the critical aggrega-
tion concentration, cac, may be established to be around 2%
ibuprofen. When the cmc is reached, the drug molecules self-
associate causing the polymer chains to coil to wrap the
micelles. This folding favors intramacromolecular bonds
and, in consequence, produces a decrease in the consistency
 436 R. Rodr´ıguez et al. / European Journal of Pharmaceutical Sciences 20 (2003) 429–438

101

100

10-1
G´´ (Pa)

10-2

10-3

10-4

10-5

101

100
G´ (Pa)

10-1

10-2

10-3

10-4

10-5
0.01 0.1 1 10 100
Angular frequency (rad/s)

Fig. 3. Effect of ibuprofen concentration on the viscoelastic behavior of PQ-

10 dispersions. Fig. 5. Schematic drawing of the effect of ibuprofen on the conformation of
cationic polysaccharides, as the drug concentration increases. In all systems
studied, the molar ratio between anionic groups of ibuprofen and cationic
groups of the polymer was above 1. When the cmc of ibuprofen is reached,
the polymer chains coil around the micelles owing to ionic and hydrophobic
interactions. This causes a strong decrease in the consistency of the system.
Increasing the number of micelles, the polymer chains uncoil and the
system recovers its initial properties.
1
of the systems and, in the case of PQ-10, even precipitation
G´ and G´´ (Pa)

(Fig. 5). A similar effect was described by Hugerth (2001) in

0.1 dispersions of dextran sulfate or carrageenan with amitripty-
line. Above cmc, the presence of more micelles makes the
0.01 aggregates and the hydrophobic regions of the polymers
more soluble. The mixed micelles become the connecting
points for transient networks (Hoffman et al., 1996) and,
0.001 therefore, the viscosity and transparency of the dispersions
rise again.
Compared to common anionic surfactants, such as SDS,
100 in which the cac with cationic polysaccharides is one to two
orders of magnitude lower than the cmc (Anthony et al.,
G´ and G´´ (Pa)

1998; Rodr´ıguez et al., 2003b), ibuprofen sorption is less

10
favored and begins nearer the cmc. The binding of ibupro-
fen molecules among themselves is preferred to the bind- ing
1 to the polymer. Similar results were reported by Ridell et al.
(1999) when the association process of this drug with two
non-ionic cellulose ethers was analyzed. The different
0.1 affinity and effects that SDS and ibuprofen induce in the
012345678 properties of the cationic polysaccharides may be related to
Ibuprofen (%) important structural differences between both amphiphilic
Fig. 4. Storage (G±, solid symbols) and loss (G±±, open symbols) moduli of
molecules. SDS has a greater surface activity and, therefore,
cationic polysaccharide dispersions (1%) containing different proportions a higher tendency to hydrophobically sorb onto the poly-
of ibuprofen (angular frequency 0.9 rad/s). mer is expected. Additionally, its sorption is facilitated by
 R. Rodr´ıguez et al. / European Journal of Pharmaceutical Sciences 20 (2003) 429–438 437

the relatively flexible apolar chain, compared to the more Table 2

rigid benzene ring of ibuprofen (Bustamante et al., 2000). Apparent viscosities and ibuprofen diffusion coefficients obtained for cationic
polysaccharide (1%)/SDS dispersions
Finally, the sulfate group has a more acidic character prone
to interact ionically. Therefore, in the case of SDS, sorp- tion Polymer SDS (%) Viscosity (mPa s) D (cm2/min)
begins at concentrations much lower than cmc form- ing PQ-4 0 41.01 (0.26) 34.1 × 10−4 (4.5 × 10−4)
hemimicellar structures with the polymer. In contrast, 0.25 36.81 (0.21) 24.9 × 10−4 (3.5 × 10−4)
ibuprofen first forms micelles into which or around which 0.30 44.01 (0.66) 19.5 × 10−4 (1.2 × 10−4)
the polymer chains distribute owing to electrostatic and hy- PQ-10 0 316.2 (0.91) 11.9 × 10−4 (2.9 × 10−4)
drophobic interactions (Fig. 5). Formation of aggregates be- 0.05 156.3 (0.42) 4.8 × 10−4 (0.6 × 10−4)
tween cationic polysaccharides and ibuprofen micelles is 0.10 147.7 (1.89) 6.3 × 10−4 (0.5 × 10−4)
more favored as the polymer has more hydrophobic residues E-14 0 589.4 (26.2) 5.9 × 10−4 (0.5 × 10−4)
and more cationic groups; i.e., cationic cellulose PQ-10 and 0.01 407.6 (2.47) 5.2 × 10−4 (0.3 × 10−4)
cationic guar gum E-14. This explains that the least relevant 0.05 285.9 (3.69) 6.0 × 10−4 (0.8 × 10−4)
changes in viscosity were observed for PQ-4 dispersions, E-261 0 2129.9 (3.3) 5.3 × 10−4 (0.7 × 10−4)
which is a polymer with the greatest content in hydrophilic 0.01 1029.3 (5.1) 5.2 × 10−4 (0.4 × 10−4)
hydroxyethyl groups. The fact that the hydroxyethyl and the 0.05 955.3 (11.5) 6.5 × 10−4 (0.1 × 10−4)
ammonium groups are separated or bound together justifies Means of three replicates (S.D.). Ibuprofen diffusion coefficient in water was
the different behavior shown by the systems based on the 180 × 10−4 (2.2 × 10−4) cm2/min.
two cationic celluloses when they interact with ibuprofen or
SDS. The presence of the free hydroxyethyl groups in PQ-4
provides enough hydrophilicity to avoid the precipitation of Edsman, 2001). In the case of cationic guar gums, the pro-
the aggregates, even when PQ-4 charges were neutral- ized portions of SDS that can be added without causing phase
and the coiled of the polymer occurred. In PQ-10, the separation are relatively small, and, in consequence, the ef-
ammonium groups are directly bonded to the hydroxyethyl fect on ibuprofen diffusion is scarce.
substituents, which may be included in the aggregates dur-
ing association with the amphiphilic molecules. This leaves 3.2. Chemically cross-linked hydrogels
the more hydrophobic unsubstituted cellulose chain exposed
to the water interface, promoting precipitation (Rodr´ıguez et 3.2.1. Drug loading
al., 2003a). For some applications, it may be interesting to keep the
viscosity and integrity of the polymer-based system
3.1.2. Ibuprofen diffusion studies constant, using the amphiphilic drug–polymer interactions
To carry out the diffusion studies, the dispersions con- to regulate the release process. In that case, chemically
taining 6% ibuprofen were selected since they combined a cross-linked hydrogels obtained by reacting the cationic
therapeutically convenient drug dose (Higgins et al., 2001) polysaccharides with ethyleneglycol diglycidylether may be
with adequate rheological properties. Suitable proportions of useful (Rodr´ıguez et al., 2003b). These hydrogels are
SDS were added to some dispersions in order to lead to the translucent, with a homogeneous surface and high consis-
maximum interaction with the cationic polysaccharides (i.e., tency and elasticity. The volume of the hydrogels when fully
those that caused the greatest increases in viscosity in the swollen in water was several times their volume as freshly
polymer alone dispersions) (Rodr´ıguez et al., 2003a) with the prepared: 7.4 for PQ-4, 9.9 for PQ-10, 3.9 for E-261, and 3.4
aim of establishing the possibilities that the addi- tion of this for E-14. These values corresponded to a hydra- tion level of
surfactant offers to modulate the properties of the systems. 70, 250, 114, and 66 g water/g dry hydrogel, respectively.
All formulations showed sustained release for more than 10 This high water affinity makes the hydrogels potentially
h and the Higuchi equation fitted the diffusion profiles well useful as main components of biocompatible systems with a
(r2 > 0.98); the diffusion coefficients being particularly low high permeability to water and small solutes (Capitan et al.,
in cationic guar gums dispersions owing to their thickening 2000).
capability (Table 2). It is interesting to note that, in the Discs of hydrogels immersed in sodium ibuprofen solu-
presence of ibuprofen, SDS did not cause a significant tions of several concentrations (1–8%) showed a decrease in
increase in the viscosity of the polymer disper- sions, but a their volume of 40%, which is related to neutralization of
decrease. Despite this effect, the diffusion coef- ficients of some ionic charges and to an increase in the ionic strength of
ibuprofen were significantly lower, especially in cationic the medium. The amount of drug sorbed linearly increased
cellulose systems, in the presence of SDS. There- fore, with the concentration of ibuprofen in the outer solution
ibuprofen may remove SDS from the binding sites of the (Fig. 6). The isotherm patterns were similar to the G-type
polymer leading to the formation of new ionic interac- tions model (Duro et al., 1999). This means that the interactions
with the polymer, hydrophobic interactions with SDS, or between the polymer and the drug are relatively weak. Nev-
mixed micelles of ibuprofen/SDS/polymer, making the ertheless, the hydrogels were able to take up a considerably
diffusion through the dispersion more difficult (Paulsson and high amount of drug, up to 15 mg/mg dry hydrogel, except
 438 R. Rodr´ıguez et al. / European Journal of Pharmaceutical Sciences 20 (2003) 429–438

16 60
PQ-10
14 PQ-4

Ibuprofen released (%)

50
12
40
10
30
8
6 20
Ibuprofen loaded (g /g dry gel)

4 10
2
0
0 0 60 120 180 240
(A) Time (min)
16
E-14
14 E-261

12
10
8
6
4
2

0
3600 3000 2400 1800 1200 600
0 1 2 3 4 5 6 7 8
(B) Wavenumbers (cm-1)
Ibuprofen (%)

Fig. 7. (A) Ibuprofen release profiles in water from PQ-10 hydrogels loaded
Fig. 6. Ibuprofen sorption isotherms on chemically cross-linked cationic
celluloses and cationic guar gums. in 6% (O), 7% (☐ ), and 8% ( ) ibuprofenO solutions; and (B) from top to
the bottom, FT-IR spectra of freshly prepared PQ-10 hydrogel, of PQ-
10 hydrogel after ibuprofen loading in 6% solution and release in water,
for E-14 hydrogels in which drug sorption was limited to and of pure ibuprofen sodium.
8 mg/mg.
ions. This explains that when the hydrogels were transferred
3.2.2. Drug release
to pH 8 phosphate buffer, all ibuprofen was released. This
Ibuprofen release profiles in water from the hydrogels
allowed to confirm the total amount of ibuprofen initially
loaded in 6, 7, or 8% ibuprofen solutions are shown in Fig.
loaded by the hydrogels.
7A. The release process reached equilibrium after 2 h, when
Fig. 8 shows the release profiles of hydrogels subse-
a 40–50% of the amount of ibuprofen loaded (60, 72, or 80
mg per disc, respectively) still remained in the hydro- gels, quently immersed in media of increasing pH, simulating the
which did not experiment significant changes in volume in vivo situation after oral administration. At pH 3 (diluted
during the process. The release occurred by Fickian diffu- HCl aqueous solution), the hydrogels just released a low
sion (Eq. (4), n = ± r > 0.98). The permanence of the
0.46 0.5, 2

drug was confirmed by IR spectroscopy (Fig. 7B). After 8 h 100

in water, the hydrogels were dried and the characteris- tic pH 3 pH 6 pH 8
bands of ibuprofen (2956 cm−1 benzene ring; 1584 and 1409
Ibuprofen released (%)

80
cm−1 ionized carboxylic groups) were still clearly vis- ible.
Also, the bands corresponding to the carboxylic groups of 60
ibuprofen were slightly moved to lower wave numbers,
suggesting ionic interactions with the polymer. Therefore,
40
only the unbound or weakly bound drug molecules are re-
leased from the hydrogel. The remaining drug molecules are
ionically trapped by the ammonium groups of the polymer 20
network, similarly to that observed by Jimenez-Kairuz et al.
(2002) for lidocaine in carbopol gels. Note that ibuprofen 0
0 60 120 180 240 300 360 420 480 540 600
concentration is, in all cases, clearly below its solubility co-
efficient in water (Cs=20%; Bustamante et al., 2000). An Time (min)
increase in pH and the presence of more ions in the medium Fig. 8. Effect of pH on ibuprofen release rate from PQ-10 (O), PQ-4 (●),
facilitate the diffusion of all ibuprofen, by acting as counter- E-14 (☐ ), and E-261 (■ ).
 R. Rodr´ıguez et al. / European Journal of Pharmaceutical Sciences 20 (2003) 429–438
proportion of ibuprofen. The lower solubility of the drug in
this media may contribute to hinder the release process
directly and, indirectly, by promoting hydrophobic interac-
tions with the polymer network. When they were transferred
to water, there was no release at all; the hydrogels behaved
differently from when they were directly immersed in wa-
ter. Finally, when the pH increased to 8, the release process
began again and finished after 6 h. The release exponents, n,
in pH 8 phosphate buffer were significantly lower than in
water, especially for hydrogels based on the polymers with a
greater content in cationic groups (0.45 for PQ-4, 0.27 for
PQ-10, 0.29 for E-14, 0.40 for E-261). This finding sug-
gests that, at least phenomenologically, the release process
is different in both media. Similar results were observed for
another NSAID molecule, diclofenac (Rodr´ıguez et al.,
2003b). At pH below the pKa of ibuprofen (4.5; Bustamante
et al., 2000), in addition to some ionic interactions, hy-
drophobic interactions are strongly promoted. This stronger
association is maintained in water and broken when the pH
and ion concentration rise.
4. Conclusions
Cationic cellulose ethers and cationic guar gums interact
hydrophobically and ionically with ibuprofen. The associa-
tion phenomena are directly related to the self-aggregation
of the drug molecules; dramatically increasing the intensity
of the interactions above the cmc. This behavior notably dif-
fers from that previously reported for the association pro-
cesses with common anionic surfactants, in which the main
changes in the properties of cationic polysaccharide systems
occur when the charges of the polymer are neutralized by the
surfactant. Ibuprofen-polymer interactions cause impor- tant
modifications in the rheological properties of the poly- mer
dispersions and considerably delay the drug diffusion rate.
Moreover, the addition to the gel of small amounts of SDS,
which causes a slight decrease in viscosity, provokes a
reduction in the values of the diffusion coefficients of al-
most 50%. In the presence of the surfactant, new bonds are
expected between the drug and the surfactant and be- tween
the mixed micelles of polymer/drug/surfactant. The
information provided by these studies was particularly use-
ful in the design of chemically cross-linked hydrogels able
to control the release process of ibuprofen as a function of
the pH of the medium. At pH 3, hydrophobic and ionic bonds
are strongly promoted and the drug is not released. The
association was partially broken in water and totally
vanished in pH 8 phosphate buffer. In summary, the inter-
action of cationic polysaccharides with anionic amphiphilic
molecules has considerable consequences on the consistency
and diffusional properties of their aqueous dispersions and
chemically cross-linked hydrogels, and highlights the need
for a profound characterization of the associative phenom-
ena as a first step in the development of drug delivery sys-
tems with these components.
439
Acknowledgements
This work was financed by the Xunta de Galicia (PGIDT
00PX120303PR) and the Ministerio de Ciencia y Tec-
nolog´ıa, Spain (RYC2001-8). The authors also express their
gratitude to the Xunta de Galicia for an equipment grant
(DOG 04/06/97) and to National Starch and Chemical Ltd.
for providing free samples of cationic celluloses.
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