Results in Pharma Sciences 3 (2013) 7–14

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Results in Pharma Sciences

journal homepage: www.elsevier.com/locate/rinphs

Surfactants modify the release from tablets made of

hydrophobically modified poly (acrylic acid)
Patrik Knöösa , Sebla Ondera , Lina Pedersenc , Lennart Piculella , Stefan Ulvenlunda , b , Marie Wahlgrenc , *
a
Division of Physical Chemistry, Lund University, Sweden
b
CR Competence AB, Lund, Sweden
c
Division of Food Technology, Lund University, Sweden

a r t i c l e i n f o a b s t r a c t

Article history: Many novel pharmaceutically active substances are characterized by a high hydrophobicity and a low water
Received 4 June 2013 solubility, which present challenges for their delivery as drugs. Tablets made from cross-linked hydrophobi-
Received in revised form 1 August 2013 cally modified poly (acrylic acid) (CLHMPAA), commercially available as PemulenTM , have previously shown
Accepted 2 August 2013
promising abilities to control the release of hydrophobic model substances. This study further investigates
the possibility to use CLHMPAA in tablet formulations using ibuprofen as a model substance. Furthermore,
Keywords:
Controlled-release tablets surfactants were added to the dissolution medium in order to simulate the presence of bile salts in the
Dissolution intestine.
Cross-linked polymers The release of ibuprofen is strongly affected by the presence of surfactant and/or buffer in the dissolution
Hydrophobically modified polymers medium, which affect both the behaviour of CLHMPAA and the swelling of the gel layer that surrounds
Surfactant–polymer interactions the disintegrating tablets. Two mechanisms of tablet disintegration were observed under shear, namely
conventional dissolution of a soluble tablet matrix and erosion of swollen insoluble gel particles from the
tablet. The effects of surfactant in the surrounding medium can be circumvented by addition of surfactant
to the tablet. With added surfactant, tablets that may be insusceptible to the differences in bile salt level
between fasted or fed states have been produced, thus addressing a central problem in controlled delivery
of hydrophobic drugs. In other words CLHMPAA is a potential candidate to be used in tablet formulations for
controlled release with poorly soluble drugs.

c 2013 The Authors. Published by Elsevier B.V. Open access under CC BY-NC-ND license.

1. Introduction shown to affect the dissolution [11,12]. Today there are few strate-
gies that address these problematic food effects; examples of formu-
A large amount of the novel pharmaceutically active substances lations of poorly soluble drugs that circumvent food effects include
can be characterized by a high hydrophobicity and a poor water sol- nano-particulate systems, e.g. with itraconazole [13,14]. In addition,
ubility [1]. Various techniques to enhance the solubility or the disso- lipids have been incorporated in the formulation to trigger fed state
lution of poorly water soluble active substances have been developed response [15–17], which then increased the solubility of the drug in
and include using solid dispersions [2–4], particle size reduction [5– the intestine and gave a higher bioavailability. Nevertheless, it is of
7], amorphous substances [8] and solubilisation using surfactants [9] importance that food effects are evaluated during development of
or complexes with, e.g., cyclodextrins [10]. However, there is still new formulations.
a pronounced need to develop formulation concepts that allow for Cross-linked poly (acrylic acid) (CLPAA), commercially available
®
controlled release of poorly soluble compounds. A common prob- as Carbopol , has been studied extensively for use in pharmaceuti-
lem during formulation of a hydrophobic drug is also the differences cal formulations, frequently because of its bioadhesive properties and
in the intestinal fluid between fasted or fed state, which has been its ability to form gels. Much of the work has focused on its use as
bioadhesive tablets [18–25], nasal applications [26–30], ocular deliv-
ery [31–33] and suppositories [34]. There has also been a considerable
effort studying the application of CLPAA in tablets [35–38], which is
approved for oral formulations. In this work the Carbopol used is
®
Carbopol 974P NF, which consist of poly (acrylic acid), cross-linked
with allylpentaerytritol.
PemulenTM , a commercially available cross-linked and hydropho-
* Correspondence to: Division of Food Technology, Lund University, Sweden, Box bically modified PAA, (CLHMPAA) has been far less studied, mainly
124 SE-221 00 Lund, Sweden. Tel.: +46 46 222 83 06; fax: +46 046 222 46 22.
E-mail address: [email protected] (M. Wahlgren).

2211-2863  c 2013 The Authors. Published by Elsevier B.V. Open access under CC BY-NC-ND license.
http://dx.doi.org/10.1016/j.rinphs.2013.08.001
8 Patrik Knöös et al. / Results in Pharma Sciences 3 (2013) 7–14

because it currently lacks a regulatory approval to be used in oral for- Table 1

Compositions of tablets used in this study. The SDS content was varied and when SDS
mulations. Most of the studies have focused on topical formulations
was added the corresponding amount of lactose (in weight percent) was removed. The
[39] but some studies have evaluated its use in tablets [35,40,41]. Fur- amount of ibuprofen was chosen from an experimental perspective in order to the
thermore, a previous study showed that CLHMPAA could yield a way match detections levels of the UV spectrophotometer.
of controlling the release of poorly soluble compounds from tablets
Ingredient Amount (wt%)
formulations [40]. The substance was assumed to be incorporated
in hydrophobic domains formed by self-assembly of the hydropho- Polymer 30
Ibuprofen 10
bic substituents, the “hydrophobes”, of the polymer. The release was
Lactose 58/56.75/54.25/50.5/45.5/33
sustained via interactions between the hydrophobic substance and Talc 1
the hydrophobes of the polymer, which resulted in an almost ideal Magnesium stearate 1
zero order release, which was not seen for a non-modified CLPAA. In SDS 0/1.25/3.75/7.5/12.5/25
this study, PemulenTM TR2 NF is used. This polymer consists of poly
(acrylic acid), cross-linked with allylpentaerytritol and is hydropho-
bically modified with grafted C10–C30 alkyl-chains.
SDS is a well-known and studied anionic surfactant, which is also
Paulsson and Edsman [42–44] evaluated the release from CLPAA
approved for oral formulations. Furthermore, SDS is also included in
and CLHMPAA polymer gels, and saw that a higher hydrophobicity
the tablet formulation in some experiments to elucidate whether this
of the drug resulted in a higher probability of interaction with the
can be used to alter the drug release. The rheology of semi-dilute
hydrophobes on the polymer. The interaction between the two could
CLHMPAA solutions, and the solubility of the polymer in the various
decrease the rate of diffusion of the drug through the gel matrix,
dissolution media, has also been studied to gain additional molecular
thus prolonging the release. They also saw that if surfactants were
insight into the release mechanisms.
added to the system, the drug molecules would partition into the
surfactant micelles to additionally slow down their diffusion. This
suggests that the release from tablets made from CLHMPAAs could 2. Materials and methods
be affected by the presence of surfactant and provides a possible way
to tune the release from tablets made of CLHMPAA. On the other 2.1. Materials
hand, pronounced surfactant sensitivity could potentially aggravate ®
problems with differences in drug absorption between the fasted and PemulenTM TR2 NF (lot no. CC11MCU893) and Carbopol 974P
fed states. NF (lot no. CC23NAB431) were kindly provided by Lubrizol Chemicals.
The dissolution process for swellable matrix tablets is generally According to the supplier, both polymers consist of poly (acrylic acid),
considered to involve solvent penetration, gel formation, swelling cross-linked with allylpentaerytritol, and contain 52–62% (Pemulen)
and disentanglement of the polymer chains [45,46]. Three different or 56–68% (Carbopol) of COOH groups. PemulenTM is also hydropho-
moving fronts have been established, i.e. the swelling front, the dif- bically modified with grafted C10–C30 alkyl-chains via ester bonds.
fusion front and the erosion front, which determine the release rate. From recorded 1 H NMR intensities of the terminal methyl groups of
These fronts have been thoroughly studied [47–49] and the principles the alkyl grafts we deduce that a 1 wt% CLHMPAA solution contains
are summarized in a very recent review [50]. Recent studies on model ca. 4 mM of alkyl grafts (hydrophobes).
tablets have shown that the rate of release of the polymer into the Sodium dodecyl sulfate (SDS) was purchased from VWR Interna-
surrounding solution (the dissolution medium) depends on the vis- tional (Sweden), lot no. 8Z0007176. In addition, Tween80 (lot no.
cosity of the so-called “gel layer” (the gelatinous semi-dilute polymer 93781) and crude bile salts (lot no. BCBJ8214V) were acquired from
solution that surrounds the tablet) at the boundary to the dissolution Fluka. The crude bile salt was a 50/50 mixture between sodium tau-
medium [47,51]. It was shown that by altering the molecular weight rocholate and sodium deoxycholate. Ibuprofen sodium salt (lot nos.
of the polymer, and hence its efficiency to viscosify the gel layer, the 038K0755 and 87H0764) was purchased from Sigma Aldrich and used
dissolution rate of the polymer could be altered. The gel layer is gener- as delivered. The CMC for SDS is 8.3 mM in pure water [55], and with
ally considered to have two functions: it slows down the dissolution a tensiometer and a de Noüy ring, we determined the CMC to 1.8 mM
of the tablet itself and it works as a transport barrier for the drug. at 37 ◦ C in 0.1 M phosphate buffered solution, pH 7.2. The CMC for
An increased thickness of the gel layer results in a slower dissolu- Tween80 is equal to 0.02 mM at 25 ◦ C [56,57]. Bile salts have poorly
tion of the tablet and a longer way for the drug to diffuse in order to defined CMC values, which differs between different environments,
be released, thus a slower drug release. In solutions of hydrophobi- nevertheless it is estimated to be between 0.5 and 2 g/L [58,59].
cally modified (HM) polymers the viscosity can be altered by addition Lactose, talc and magnesium stearate were of analytical grade. For
of surfactant [52,53]. Moreover, added surfactant can solubilise such granulation fluid a (70:30) mixture of ethanol (99.5%) and 0.001 M
HM-polymers that, owing to extensive hydrophobic association, are aqueous HCl was used.
not soluble in water [52,54]. These facts indicate that the release from
HM-polymer tablets can be altered by the presence of surfactant. 2.2. Tablet preparation
This study further investigates the possibility to use CLHMPAA in
tablet formulations manufactured by pharmaceutically relevant unit Tablets were prepared with compositions as specified in Table 1,
processes. Ibuprofen is used as a model drug substance due to its hy- and the manufacturing procedure was the same for all compositions.
drophobic properties, in order to study the effects from hydrophobic First, the dry ingredients, lactose, polymer and ibuprofen (and SDS,
interactions. Ibuprofen is not considered (during our experimental where applicable) were mixed in an intensive mixer (Kitchen Aid),
conditions) poorly soluble, which circumvents solubility issues. for 5 min. The granulation process started with gently spraying gran-
The focus of this study is on the effects of adding surfactants, ulation fluid over the powder, with interruptions to allow the fluid
similar to the differences in the intestinal fluid between fasted or fed to absorb. The procedure was continued until the desired properties
states. In the biological system the tablets might be affected by surface of the granulation were achieved. The granulation was then sieved
active compounds such as bile salts. In this work we have examined through a 2 mm sieve, and if the particle size was too large, a food-
the effects from addition of different types of surfactants, which either processer was used to further reduce it. The granulation was then
are allowed for oral use or are endogenous substance from bile. A dried in an oven at 50 ◦ C overnight and was afterwards sieved again
common model surfactant, sodium dodecyl sulfate (SDS), was chosen through a 2 mm sieve. The dried granulation was mixed with talc and
to further examine the general effects of surface active compounds. magnesium stearate in a cone blender for 2 min after each addition.
 Patrik Knöös et al. / Results in Pharma Sciences 3 (2013) 7–14 9

The tablets were manufactured with a single-punch tableting ma- solution, 2 M NaOH-solution was used to adjust the pH to 7, after
chine, Diaf (Denmark), to a weight around 400 mg. Appropriate set- addition of polymer. Care was taken to ensure that the same amount
tings were applied to ensure a good hardness and weight of the tablets. of NaOH was added to each sample, yielding equal ionic strength.
Hardness and friability were measured according to US Pharmacopeia The pH of each sample was confirmed prior to analysis. After addi-
methods. All tablets achieved a hardness over 5 kp and a friability less tion of polymer all samples were agitated and put on a tilt table until
than 1%, except for those containing high amounts of SDS (≥10 wt%), analysed. The samples were also repeatedly mixed manually with a
which were too soft (hardness <5 kp) and had a poor friability (>1%). spatula and centrifuged directly afterwards. All samples were mixed
for 1 week to ensure that equilibrium had been reached. Prior to anal-
2.3. Dissolution experiments ysis, the samples were centrifuged to eliminate air bubbles formed
during the mixing. All samples were prepared in triplicate.
Dissolution experiments were carried out at 37 ◦ C in a USP dissolu-
tion apparatus II (Prolabo Intelligent dissolution tester Novakemilab, 2.4.2. Oscillatory rheology measurements
Sweden) with a paddle speed of 100 rpm. Samples were continuously The measurements were carried out on a controlled stress
withdrawn and transferred by means of a pump to a spectropho- rheometer (StressTech IMP5040, Reologica, Viscotech). Cone-plate
tometer (Cary 50 Bio UV–visible, Varian, Australia) which measured symmetry with a diameter of 40 mm was used and the temperature
the ibuprofen concentration in the vessels as the absorption at λ was set to 37 ◦ C. All experiments started with equilibration of the
= 222 nm. From the measured UV absorbance the concentration of sample for 60 s, followed by a stress sweep at 1 Hz between 0.2 and
ibuprofen and, hence, the fraction released in the dissolution medium, 200 Pa in 50 logarithmic steps. Directly afterwards a frequency sweep
could be determined. between 0.005 and 10 Hz at a constant stress of 1 Pa was performed.
Each USP vessel was filled with 800 mL of dissolution medium. The frequency-dependent complex viscosity (η*) was obtained from
The media used were 0.1 M phosphate buffered solution, pH 7.2, and  1/2
(G  ) + (G  )
water deionised in a Milli-Q water apparatus. The pH of the water so- 2
∗ G∗
lution was not monitored during dissolution nevertheless it is likely η = = (2)
ω ω
that pH will change during dissolution. Tween80 and bile salts were
added to buffered solution in the following concentrations 10 g/L and where G is the storage modulus, G is the loss modulus and ω is the
7.14 g/L respectively (similar to the conditions in the intestine at fed frequency of oscillation.
state [60]). For SDS varying amounts were added, yielding concentra-
tions between 0–10 mM (phosphate buffered solution) and 0–20 mM 3. Results
(Milli-Q water). The amount of SDS added to the tablets represents
a concentration in the bath of maximum 0.4 mM, which is below 3.1. Dissolution of HMPAA tablets in different media
the CMC for SDS. Tablets were weighed prior to the start of the ex-
periments. From this the total amount of ibuprofen in a tablet was The release of ibuprofen from tablets made from CLHMPAA is gen-
calculated. erally characterized by a slow and linear release profile (Figs. 1 and
For tablets dissolving in Tween80 and crude bile salts the ab- 2) throughout the dissolution process and the release was faster in
sorption from the spectrophotometer could not be used due to the water than in buffered solution Addition of surfactant to the dissolu-
large absorbance from the solutions. Instead aliquots (V = 1 mL) were tion medium slowed down the release further, however retaining the
manually withdrawn from each vessel at specified time intervals and linear release. The different surfactants used reduce the release rate
analyzed with HPLC (HP Series 1050), using a flow of 0.4 mL/min on in a similar manner and to a similar extent, in Fig. 1, all surfactants
a reversed phase Acclaim RLSC C18 2.2 μ m, 120 Å, 2.1 × 50 mm2 are added in concentrations over the CMC. Examining the dissolv-
column. The HPLC detected the ibuprofen as the UV absorption at ing tablets visually shows that the tablets form larger gel layer upon
λ = 222 nm. For samples containing Tween80, an isocratic solution addition of buffer and surfactants. However, upon addition of bile
with 40% ACN and 60% water with 0.1% acetic acid was used. Samples salts a clear gel layer is not formed, instead the tablets were cloudy
containing bile salts were mixed with AcN prior to analysis (50/50 nonetheless swollen. Moreover studies have been performed, where
mixture) and analysed with an isocratic solution of 35% ACN and 65% the release of lactose from the tablets has been quantified using a new
water with 0.1% acetic acid.
 ns analytical method, which will be published soon. These show that the
(C ibu × (V 0 − V s ×ns ) + (V s ×C s )) lactose (a hydrophilic model substance) is quickly released from the
% Release = (1)
mibu, tablet tablet, and the release is less affected by the presence of surfactants.
Examining the release rate for different concentrations of SDS
The released amount (%released) was calculated according to Eq. there is a discrepancy between the buffered solution and water below
2.5.1, where the concentration of ibuprofen according to the HPLC is concentrations of 7 mM (Fig. 2). On the other hand, above 7 mM SDS,
given by Cibu and the initial volume of the vessel is V0 ( = 800 mL). Vs the rate was similar and very slow in both media and here the tablets
and Cs denote the volume ( = 1 mL) and the concentration in the were not fully dissolved after 67 h. In some cases the tablets appeared
samples respectively and the number of samples is denoted ns . The to release more than 100% when fully dissolved; this is most likely
amount of ibuprofen in the tablets is given by mibu,tablet . All experi- due to solvent evaporation during the extended dissolution time. The
ments, if not stated otherwise, were performed at least two times in amount of polymer in the tablets is high in these experiments; a low-
order to validate reproducibility. ering of the polymer concentration will increase the release rate but
also make the experiments sensitive to polymer concentration. Thus
2.4. Rheology all the work done here is performed at a polymer concentration high
enough to avoid this sensitivity.
2.4.1. Sample preparation In order to compare the release rates for different concentrations
Rheology experiments were conducted on systems of 1 wt% CLHM- of SDS in the various dissolution media, the release rate at 20% re-
PAA in either deionised water or in 0.1 M phosphate buffered solution leased amount (R-20) was evaluated from each release profile by
at varying concentrations of added SDS. The procedure was the same a linear fit to 10 data points centred around 20% released amount.
for both types of dissolution media. A stock SDS solution was diluted The choice of 20% is somewhat arbitrary, but owing to a very slow
to the desired concentration, and then CLHMPAA was added to give release, a few experiments had reached less than 50% of released
1 wt% concentration of polymer. For samples prepared in buffered ibuprofen at termination, see Fig. 2. The R-20 data are collected in
10 Patrik Knöös et al. / Results in Pharma Sciences 3 (2013) 7–14

Fig. 1. Release of ibuprofen from CLHMPAA tablets into different solutions containing Fig. 3. Slopes of ibuprofen release profiles at 20% released amount for tablets dissolving
pure water and buffer (0.1 M, pH = 7.2) as well as buffer with added surfactants in buffered solutions (0.1 M, pH = 7.2, filled) and water (open) at varying concentrations
(SDS, Tween80 and bile salts) as noted in the figure. Each dataset represents one of SDS added to the dissolution media. Each symbol represents one measurement and
measurement and is shown as representative data. The released amount is normalized the lines are drawn through the average values. Vertical lines show the critical micelle
against the released amount for fully dissolved tablets, i.e. released amount at tend = concentrations of SDS in buffered solution and in pure water.
100%. Lines without data points represent measurements every 20th minute up to 6 h
and after that measurement each hour.
developed already without SDS, and no eroding particles were de-
tected visually at any SDS concentration.

3.2. Physico-chemical behaviour of CLHMPAA in different media

In order to better understand the dissolution and drug release be-

haviour in the various systems, we performed additional studies of
the physico-chemical behaviour of CLHMPAA in the various media.
One series of simple experiments addressed the solubility of CLHM-
PAA. From a physico-chemical point of view, PemulenTM consists of
Fig. 2. Release of ibuprofen from CLHMPAA tablets in water (A) and buffered solution huge cross-linked polymer molecules that may either dissolve in, or
(0.1 M, pH = 7.2, B) without and with added SDS at the indicated concentrations. The phase separate from, a given solvent. To test this we made up a se-
release is compared to the release of ibuprofen without addition of surfactant (0 mM ries of dilute mixtures of CLHMPAA in the various dissolution media.
SDS). Each dataset represents one measurement and is shown as representative data.
The concentration (0.015 wt%) of these dilute mixtures was chosen
to be equal to the concentration at complete dissolution in the dis-
solution experiments. The samples were then agitated and put on a
Fig. 3, which clearly illustrates the effects of the buffer and/or sur- tilt-table for a period of 1 week and were subsequently subjected to
factant added to the dissolution media. In either medium, the release centrifugation (1 h at 5000 rpm).
of ibuprofen was hardly affected by the presence of surfactant in a CLHMPAA did not dissolve in pure water, but formed a cloudy
low-concentration plateau region, below a concentration of ca. 2– dispersion of swollen gel particles that could be separated by cen-
3 mM SDS. Above the latter concentration, the ibuprofen-release rate trifugation. On addition of 1–2 mM SDS, the cloudiness disappeared,
decreased rapidly with added SDS until a second high-concentration but centrifugation still resulted in the separation of the polymer, this
plateau was reached. The concentration of SDS at the onset of the time as a clear, gelatinous bottom phase. At and above 5 mM SDS in
high-concentration plateau coincides quite well with the critical mi- water, finally, the polymer appeared totally dissolved and no polymer
celle concentration, CMC, of SDS in both buffered solution and pure separated out on centrifugation. In buffered solutions clear samples
water. There was a strong effect of the buffer at zero and low concen- were obtained both with and without SDS, but centrifugation resulted
trations of SDS, whereas the release rate at the high-concentration in the separation of a clear, polymer-rich bottom phase at SDS con-
plateau was insensitive to the presence of the buffer. centrations at or below 2 mM. Above 2 mM SDS in buffered solution,
The tablets were observed visually during dissolution in the CLHMPAA was again found to be soluble.
medium with SDS and sample tablets were also taken out of the We also measured the viscosity of CLHMPAA in the various media.
dissolution medium. All dissolving tablets were surrounded by trans- The measurements were done at higher concentrations (1 wt%) of the
parent gel layers and in the middle of the tablet a white “core” could polymer, to probe conditions that should be more relevant for the gel
be seen; closer examination showed that this core was not solid but layers surrounding the tablets. Since the concentration of carboxylic
rather had a sponge-like texture. The gel layers of the tablets gen- acid groups from the polymer was comparable to the concentration
erally increased in thickness with increasing SDS concentration, but of phosphate buffer in the buffered systems, the buffer alone did not
large differences in the dissolution behaviour in water and buffered succeed in maintaining a pH around 7. Therefore, the pH for these
solution were observed at low SDS concentrations. In water a clear systems was adjusted to 7 ± 0.2 by addition of 2 M NaOH, again to
but very thin gel layer developed and the tablet had a rough surface mimic the situation in a gel layer exposed to a large reservoir of buffer
from which semi-swollen particles, visible to the naked eye, eroded at pH 7.2. The resulting systems were in all cases highly viscous.
during dissolution. The latter feature disappeared when the SDS con- Fig. 4 shows the complex viscosities at 0.2 Hz of 1 wt% CLHM-
centration had reached the high-concentration plateau; here a thick, PAA in water and buffered solution plotted against the concentration
smooth gel layer developed. In buffered solution, a sizeable gel layer of added SDS. In both media, the viscosity varied significantly with
 Patrik Knöös et al. / Results in Pharma Sciences 3 (2013) 7–14 11

Fig. 4. Complex viscosity* (η*) (at 0.2 Hz) for 1 wt% CLHMPAA in buffered solution Fig. 5. The release of ibuprofen from CLPAA tablets in buffered solution (0.1 M, pH =
((0.1 M, pH = 7.2, pH = 7) (filled) and water (open) with increasing SDS concentration. 7.2) containing pure buffer (0 mM SDS), 3 mM and 10 mM SDS. Each dataset represents
Error bars indicate the standard deviation (n = 3). one measurement and is shown as representative data.

the SDS concentration, clearly revealing an interaction between SDS

and CLHMPAA. Mixtures prepared in water solution consistently dis-
played a lower viscosity compared to the buffered systems, but the
two sets of results approach each other at high surfactant concentra-
tions.

3.3. Additional dissolution experiments

3.3.1. Tablets of non-modified cross-linked PAA

For reference, we also studied the release of ibuprofen into
buffered solution from dissolving tablets made from non-modified
CLPAA, see Fig. 5. The latter behaved differently from those made
from CLHMPAA. The CLPAA tablets developed a very thin gel layer
and disintegrated faster, with small gel particles eroding continu-
ously from the tablets. These tablets were fully dissolved after ca.
340 min. Visually there was no obvious effect of SDS added in the
dissolution medium on the size and shape of the gel layer, nor on the
erosion of gel particles. The non-modified tablets also gave a faster
release of ibuprofen, compared to the CLHMPAA tablets, but the re-
lease was still linear. Although the effects of added SDS on the release Fig. 6. The release of ibuprofen in buffered solution (0.1 M, pH = 7.2) from tablets of
are largely lost for tablets without hydrophobes, closer examination CLHMPAA containing 7.5 wt% SDS (SDS in tablet), compared with tablets with no SDS
(without SDS). The lines represent repeat measurements on different tablets performed
reveals a small decrease in the release rate on addition of surfactant
at the same time and illustrate the experimental reproducibility. Lines represent mea-
to the release medium. surements every 20th minute up to 6 h and after that measurement each hour.

3.3.2. CLHMPAA tablets containing added SDS

In a final set of experiments, we studied the dissolution and re-
lease from CLHMPAA tablets that also contained SDS. Small additions
of SDS to the tablets did not result in large changes in tablet proper- Further investigating the effects of surfactants on the release, SDS
ties during production, except an increased sensitivity during solvent was added also to the medium during the dissolution of SDS-loaded
addition during granulation, and tablets with satisfying properties tablets. Two different concentrations of SDS in the buffered solutions
were achieved. However, if the amount of SDS in the tablet was in- were used, one at the low-concentration plateau seen in Fig. 3 and one
creased above 7.5 wt%, a soapy granulation was obtained, which with at the high-concentration plateau. As illustrated in Fig. 7, there were
our equipment resulted in poor tablets with a low hardness and poor no apparent effects on the ibuprofen release from the SDS-loaded
friability. In all cases the total amount of SDS added to the tablets tablets of adding SDS to the dissolution medium: the already slow
was lower than the lowest total amount of SDS that was added to the release was retained.
dissolution media in the previous set of experiments. To further investigate surfactant effects the release from CLH-
The effect of adding SDS to the tablet on the release of ibuprofen PMPPA tablets with SDS in media containing Tween or Bile salt was
into buffered solution was similar to the effect of adding surfactant investigated. As can be seen the profile is quite similar as for the pure
to the release medium. A slow linear release was observed that ex- buffer or SDS media. The release could be somewhat slower but one
tended over days, see Fig. 6. Adding increasing amounts of SDS to the should keep in mind that these experiments were performed with
tablet decreased the release rate, until a point where the tablet and another batch of tablets and using a different analytical method. It
granulation properties became unsatisfying. SDS added to the tablet has been observed that the UV analyses usually give a final amount
increased the thickness of the gel layer, again similar to the effect of released that is slightly above 100% but that the HPLC measurements
adding SDS to the dissolution medium. normally only give 100% of release.
12 Patrik Knöös et al. / Results in Pharma Sciences 3 (2013) 7–14

of surfactant, solubilisation of the hydrophobes in the surfactant mi-

celles make the CLHMPAA/SDS aggregates soluble in water both with
and without buffer.
We note that the mixtures investigated by rheology in Fig. 4 are not
directly comparable to the dissolving tablets, since the latter systems
are connected to a large reservoir of surfactant and buffer. Owing to
the binding of surfactant to the HMPAA hydrophobes, the total con-
centration of surfactant in the outer part of a gel layer surrounding
a tablet may be substantially higher than the concentration in the
surrounding reservoir. On the other hand, our simple solubility tests,
which were made in dilute systems, should be directly comparable to
the tablet dissolution experiments. In the solubility tests, we found
that both in water and in buffered solution, a complete dissolution
of CLHMPAA required surfactant concentrations of the order of the
surfactant CMC or higher. We also saw that the CLHMPAA-rich phase
that separated out at zero or low levels of surfactant was much more
swollen in buffer than in unbuffered water, a difference that we at-
tribute to the difference in polymer charge.
Fig. 7. R-20 values in buffered solution (0.1 M, pH = 7.2) for tablets of CLHMPAA that
contained indicated amounts of added SDS. Points marked with an asterix represent
The varying water solubility of HMPAA and its complexes with
tablets that did not fulfil the requirements regarding hardness and friability. Error bars SDS, and the varying water uptake of those complexes that separate
represent the standard deviation of the measurements (n > 2). out of the solution, should have profound consequences for the dis-
integration of the tablets and the drug release. For dissolution media
at high surfactant concentrations we have the common case of a sol-
uble polymer that can swell indefinitely in the dissolution medium.
4. Discussion The situation should then be similar to, e.g., poly (ethylene oxide)
tablets dissolving in water, which have been studied in detail [47,51].
The aim of the present study was to elucidate the consequences of For the latter systems, it was concluded that the disintegration of
hydrophobic modification on the behaviour of PAA-based tablets in the tablets was governed by the viscosifying efficiency of the poly-
different media. Our major findings may be summarised as follows. mer. For the very viscosifying HMPAA studied here (see Fig. 4), a
(1) Hydrophobic modification generally gives rise to a slower ibupro- thick gel layer develops and tablet disintegration and drug release
fen release from a CLPAA-based tablet, and to a marked surfactant become very slow. At high surfactant concentrations, the observed
sensitivity of the release. (2) Added surfactant, either dissolved in the plateau release rate (see Fig. 3) then suggests that the viscosity of the
medium or incorporated in the tablet, makes the release even slower system has become insensitive to further surfactant addition. This is
until a plateau is reached at high surfactant levels. (3) With surfactant indeed expected when the concentration of surfactant in the medium
incorporated in the tablet, the ibuprofen release becomes insensitive has reached CMC; then free micelles form, the surfactant monomer
to surfactant added in the dissolution medium. We will now attempt concentration remains approximately constant, and there is little ad-
to understand these features in the light of prior knowledge as well ditional surfactant binding to the complex.
as the additional observations made in this study. At low surfactant concentrations, CLHMPAA is not soluble in the
Established knowledge on aqueous mixtures of HM-polymers and investigated media, and this means that the gel layer around the
surfactants may be summarized as follows [54]: the hydrophobes of tablet can only swell until it reaches the composition of the polymer-
HM-polymers typically self-associate in water, leading to a high vis- rich phase that would separate out at equilibrium when polymer is
cosity of their semi-dilute aqueous solutions, but also to a decreased added to the same medium. When such a gel layer is subjected to
water solubility. Charged HM-polymers are more soluble than un- shear, pieces of the swollen but insoluble gel layer will be sheared
charged ones, other factors being equal. When surfactant is added to off, as was indeed observed in the release experiments. The erosion
a HM-polymer in water, the surfactant molecules enter into the ag- of small gel particles not only speeds up the disintegration of the
gregates of the hydrophobes, forming mixed micelles of hydrophobes tablet itself, but also the release of the drug, since the drug release
and surfactant molecules. At low fractions of incorporated surfac- from many small gel particles, with a large specific surface area, is
tant molecules, their effect is mainly to strengthen the pre-existing much more rapid than the release from a single macroscopic tablet.
hydrophobic association between the polymer molecules. With in- A comparison between surfactant-free water and buffered solution
creasing levels of surfactant, however, the number of mixed micelles as dissolution media show that the maximum degree of swelling of
increases and, eventually, all hydrophobic cross-linking is lost as the the concentrated phase is also important for the tablet disintegration
polymer hydrophobes are solubilised in the abundant surfactant mi- and the drug release. In the buffer the PAA chains are partly charged
celles. and the maximum swelling is larger, compared to the situation in un-
In Fig. 3, the rheology of 1 wt% CLHMPAA in buffered solutions at buffered water. This results in a thicker gel layer in buffered solution,
pH 7 illustrates the typical response of a water-soluble HM-polymer leading to a less efficient disintegration of the tablet by shear (less
to added surfactant [52–54]: at low levels, the viscosity increases polymer is removed per unit time), and a slower drug release.
(strengthening of the hydrophobic association) but eventually, the An alternative way to produce soluble HM-polymer/surfactant
viscosity decreases again, owing to a dissolution of the hydrophobic complexes is to incorporate a sufficiently high level of surfactant in
polymer–polymer association. The water solubility of the HMPAA is the tablet, as in the release experiments in buffered solution sum-
here achieved by a large fraction of charged carboxylate groups at marized in Figs. 6–8. Although surfactant should be released from
pH 7. In unbuffered water, on the other hand, the initial rheological the tablet and thus from the complexes, this is a slow process since
response of the essentially uncharged CLHMPAA to added surfactant the concentration of uncomplexed surfactant in the tablet gel layer
is typical of a system with water-swollen, but insoluble, hydrophobi- must be of the order of CMC (2 mM in buffered solution) or less. With
cally modified polymer aggregates. Here, the initial strengthening of sufficient levels of surfactant in the tablets, the release also becomes
the hydrophobic association leads to a de-swelling of the polymer– insensitive to the presence of surfactant in the bulk (Fig. 8).
surfactant aggregates and, hence, a decrease in viscosity. At high levels
 Patrik Knöös et al. / Results in Pharma Sciences 3 (2013) 7–14 13

extended dissolution time. This suggests that the potential of CLHM-

PAA and surfactant in tablet formulations is high and that further
studies should be conducted. This includes optimising the content of
Pemulen to give a desired time frame of release as well as obtaining
approval for oral use of the polymer.

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