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Effect of the Interaction Between an Ionic Surfactant and Polymer on the

Dissolution of a Poorly Soluble Drug

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DOI: 10.1208/s12249-018-1125-x

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DOI: 10.1208/s12249-018-1125-x

Research Article

Effect of the Interaction Between an Ionic Surfactant and Polymer

on the Dissolution of a Poorly Soluble Drug

Vaishnavi Parikh,1,2 Suhas G. Gumaste,1 and Shivaji Phadke1

Received 9 May 2018; accepted 15 July 2018

Abstract. Surfactants are commonly incorporated in conventional and enabled formula-

tions to enhance the rate and extent of dissolution of drugs exhibiting poor aqueous
solubility. Generally the interactions between the drug and excipients are systematically
evaluated, however, limited attention is paid towards understanding the effect of interaction
between functional excipients and its impact on the performance of the product. In the
current study, the effect of potential interaction between a nonionic polymer binder,
povidone, and anionic surfactant docusate sodium on the rate and extent of dissolution of
a drug exhibiting poor aqueous solubility was evaluated by varying the proportions of the
binder and the surfactant in the formulation. Potential complexation or aggregation between
the excipients was investigated by fluorescence spectroscopy and zeta potential measure-
ments of the aqueous solutions of docusate sodium, povidone, and sodium lauryl sulfate
(SLS). The rate and extent of drug release was found to decrease with an increase in the
proportion of docusate sodium and povidone in the formulations. Difference in magnitude of
surface charge (zeta potential) of docusate sodium in presence of povidone indicated
potential surfactant-polymer aggregation during dissolution which was corroborated by
CAC/CMC values derived from fluorescence spectroscopic measurements. The decrease in
the rate of drug release was attributed to an increase in the viscosity of the microenvironment
of dissolving particles due to the interaction of docusate sodium and povidone in the aqueous
media during dissolution. These findings highlight the importance of systematic evaluation of
the interaction of ionic surfactants with the polymeric components within the formulation to
ensure the appropriate selection of the type of surfactant as well as its proportion in the
formulation.
KEY WORDS: polyvinylpyrrolidone; docusate sodium; sodium lauryl sulfate; dissolution; anionic
surfactants; polymer-surfactant aggregation.

INTRODUCTION Surfactants are typically selected based on their physical

Drug molecules with aqueous solubility lower than 100 μg/
mL generally present dissolution rate limited absorption. The
limited dissolution rate arising from low solubility frequently
results in the low and variable bioavailability of orally admin-
istered drugs. Due to their amphiphilic nature, surfactants
enhance the wettability of hydrophobic drugs by lowering the
surface tension at the interface of the dissolving drug particles
and thus enhance the rate of drug release (1–7). As such,
surfactants are widely used in drug delivery systems (8–10).
Additionally, surfactants are also utilized in development of
in vitro dissolution methods to allow complete solubilization of
poorly soluble drugs in the dissolution media (11).
1
Product Development, Genus Lifesciences Inc., 700N Fenwick
Street, Allentown, Pennsylvania 18109, USA.
2
To whom correspondence should be addressed. (e–mail:
vrshah1987@gmail.com)
properties, i.e., stability at the desired processing conditions,
ease of incorporation in the dosage form, toxicity, compati-
bility with the API and their dissolution rate enhancement
potential. Binary drug-excipient compatibility studies are
usually conducted to determine the compatibility between
the excipients and the API, and accelerated and long-term
stability studies are conducted to determine the overall
stability of the formulation. However, limited attention is
paid to the possible interactions between the excipients and
their potential impact on the product stability and perfor-
mance, especially in the case of surfactants, due to the limited
literature available on their effect on product performance
and stability. If such interactions remain undetected in early
stages of development they can prove to be difficult to resolve
since major changes in the formulation composition can lead
to a significant delay the development process. For example,
presence of aldehyde impurities in excipients may lead to
crosslinking of gelatin capsule shells and impact the rate and

1530-9932/18/0000-0001/0 # 2018 American Association of Pharmaceutical Scientists


extent of dissolution from these formulations (12,13). Any
change in the excipient quantity contributing to the cross-
linking can alter the in vitro dissolution profile of the formula-
tion. Similarly, certain liquid excipients and surfactants are
known to extract moisture from the capsule shell upon long term
storage, making the shells brittle and thus leak (14).
Ionic surfactants are also known to aggregate with polymers in
aqueous solutions which may lead to enhancement or even
retardation of drug release during in vitro dissolution. Nilsson and
coworkers demonstrated the aggregation of HPMC and sodium
dodecyl sulfate (SDS) (15). Their studies showed that at low
concentrations of HPMC and SDS, there is no interaction between
the two components. At a certain concentration, termed as CAC
(critical aggregation concentration), SDS starts to adsorb on the
surface of HPMC to forms clusters or aggregates. This concentra-
tion of the surfactant is below the CMC (critical micelle
concentration) of the surfactant. At concentrations above CAC,
the surfactant continues to adsorb on the polymer chains until the
binding sites on the polymer are completely saturated (Cs) after
which the free monomers of the surfactant increase with further
increase in surfactant concentration up to CMC, at and above
which micelles are formed in such a system. Numerous studies
demonstrating such interactions between polymers such as
ethylhydroxyethyl cellulose, poly(vinylpyrrolidone), poly (ethylene
oxide), hydroxyproplymethyl cellulose, and hydroxypropyl cellu-
lose and ionic surfactants like SLS, gemini, and carboxylate-based
anionic dimeric surfactants have been reported (16–21). Qi et al.
showed the effect of polymer-surfactant complexation on drug
solublization during dissolution from solid dispersions (19). Simi-
larly, Gebrehemskel et al. showed the impact of surfactants on the
dissolution of a poorly water soluble drug from solid dispersions
prepared with different polymers (22). In both these studies, a
variation in dissolution rate or solubility of the drugs due to
surfactant-polymer interactions was reported. Polymer and surfac-
tant co-exist in several drug products. With well-documented
literature on surfactant and polymer aggregation it is vital that the
effect of proportion of surfactant and polymer in the formulation
on rate and extent of dissolution of the drug is investigated during
the product development process.
In order to enhance the dissolution rate of a drug exhibiting
poor aqueous solubility (4.19 mg/l), docusate sodium was
incorporated as a surfactant in the formulation. Due to its anionic
nature and potential interaction with povidone, systematic
investigation of the effect of docusate sodium on the rate and
extent of dissolution by varying the levels of docusate sodium
(DS) and povidone (PVP) in the formulation were conducted. In
order to determine the impact of the concentration of surfactant
pre-dissolved in the dissolution media on drug release, dissolution
studies in presence of sodium lauryl sulfate (SLS) were con-
ducted. CAC/CMC of docusate sodium in presence of povidone
were determined by fluorescence spectroscopy using the fluores-
cent probe, pyrene. Potential interactions between povidone,
docusate sodium, and SLS were also investigated by analyzing the
zeta potentials of their aqueous solutions.
MATERIALS AND METHODS
Materials
Corn starch was obtained from Ingredion (Indianapolis,
IN). Lactose Monohydrate NF was obtained from DFE
Parikh et al.
Pharma (Paramus, NJ). Povidone, NF (Plasdone K 29–32)
was obtained from Ashland Specialty Ingredients (Texas City,
TX). Docusate Sodium, USP was obtained from Solvay
(Willow Island, WV). Talc, USP was obtained from Barrett’s
Mineral Inc. (Dillon, MT). Magnesium Stearate, NF was
obtained from Mallinckrodt Chemicals, Inc. (St. Louis, MO).
Dodecyl sulfate sodium salt (SDS), was obtained from
Thermo Fisher Scientific, (Bridgewater, NJ). Pyrene was
obtained from Acros Organics (Bridgewater, NJ).
Methods
Preparation of Tablets for Dissolution Studies
Tablets were manufactured using the wet granulation
process described as follows. The proportion of API, lactose
(20–40% w/w), corn starch (30–50% w/w), talc (0.25–1.0% w/w),
and magnesium stearate (0.25–1.0% w/w) was kept constant for
all the formulations while the amount of povidone and docusate
sodium were varied to determine their impact on the rate and
extent of dissolution. The values provided in parenthesis specify
the ranges that were considered during the development of the
formulation. The proportion of each of these ingredients, with
the exceptions of docusate sodium and povidone, was kept
constant for the formulations prepared in the current studies.
Table I denotes the formulation numbers and the corresponding
levels of povidone and docusate sodium in the respective
formulations. The API, lactose, and corn starch were dry
blended prior to granulation. The blend was granulated using
an aqueous solution of povidone and docusate sodium. The
resultant granules were dried at 60 °C in a tray dryer till the
desired moisture content was achieved, followed by milling and
blending with talc and magnesium stearate prior to compression.
Tablets were compressed using a BVA Hydraulic Press (BVA
Hydraulics, Kansas City, MO) with 10 mm standard concave
round punches at a pressure of 1750 psi to yield tablets with
hardness between 4 to 5 kP.
Dissolution Studies
Tablets prepared according to the compositions de-
scribed in Table I were subject to dissolution studies in a
USP Type II (paddle) dissolution apparatus set at 37 °C and
a paddle speed of 50 RPM for the first 60 min and 250 RPM
for additional 15 min. Dissolution tests were performed in
1000 mL dissolution media containing 0.5% or 2% w/v SLS
dissolved in deionized water. During the dissolution method
development studies, complete dissolution of the intended
Table I. Composition of the Formulations Prepared for Dissolution
Studies. Apart from the Ingredients Listed in the Table, Each
Formulation Consisted of API, Lactose Monohydrate, Corn Starch,
Talc, and Magnesium Stearate; the Proportion of These Ingredients
Was Kept Constant for All the Formulations
Formulation code F1 F2 F3 F4 F5 F6
Povidone (% w/w) 2.5 2.5 2.5 5 5 5
Docusate sodium (% w/w) 0.075 0.213 1.4 0 0.025 0.075
Effect of the Interaction Between an Ionic Surfactant and Polymer

dose of the API, 150 mg, could not be achieved in media RESULTS
containing deionized (DI) water or non-buffered aqueous
solutions at pH 1.2, 4.5, or 6.8. Therefore, media containing
Dissolution Studies
a minimum of 0.5% w/v SLS were used during the
dissolution test. The extent of drug release during dissolu-
For the development of the dissolution method, dissolu-
tion was determined using a multi-channel, fiber optic-based
tion test of neat API was conducted in deionized water. The
UV spectrometer system, Opt-Diss 410 (Distek Inc., North
extent of dissolution was found to be nearly negligible in
Brunswick, NJ) consisting of a CCD (charged coupled
deionized water (< 5%) due to its extremely low aqueous
device) type detector. The fiber-optic arch probes (with a
solubility. Further, formulation F3 was subject to dissolution
path length 10 mm) were suspended in the dissolution baths
in a USP Type II apparatus at a paddle speed of 50 rpm in
and data was collected every 15 s throughout the duration
various media. The media used were deionized water, 0.1 N
of dissolution test. Detection wavelength was set at 263 nm
HCl, buffer solutions at pH 4.5, 6.8, 7.5, and aqueous
and the data was analyzed using the Opt-Diss™ software
solutions of SLS at 0.25, 0.5, 1, and 2% w/v concentrations,
(Distek Inc., North Brunswick, NJ). The coefficient of
which exhibited, respectively, 58, 53, 56, 48, 46, 47, 97, 97, and
determination in the concentration range evaluated with
94% drug release at the end of 60 min of testing. It could be
this setup was found to be 0.97.
seen that complete drug release could only be achieved in
media containing a minimum of 0.5% w/v SLS, and therefore,
Fluorescence Spectroscopy
further studies were conducted in dissolution media contain-
ing 0.5% or 2% w/v SLS.
Fluorescence spectroscopy was used to determine
CAC, Cs, and CMC of docusate sodium in presence of
povidone. Fluorescent probe, pyrene, exhibits different Dissolution Tests in 0.5% w/v SLS Medium
fluorescence behavior in non-micellar and micellar solu-
tions (23,24). Docusate sodium and povidone solutions at Figure 1a shows the extent of drug release from tablets
various concentrations of docusate sodium, 2.5% w/v or prepared from formulations F1, F2, and F3 containing,
5% w/v of povidone, and 0.1 μM of pyrene were respectively, 0.075, 0.213, and 1.4% w/w docusate sodium
prepared. The solutions were characterized by fluores- with 2.5% w/w povidone. At the end of 20 min of testing,
cence spectroscopy at 25 °C using Tecan i3 fluorescence formulations F1, F2, and F3 exhibited 78%, 48%, and 60%
spectrophotometer (Tecan Group Ltd., Morrisville, NC). drug release, respectively. Nearly complete drug release, ca.
The excitation wavelength of 330 nm was adjusted and 90% was seen from each of these formulations at the end of
emission spectra for pyrene were obtained from 370 to 60 min of dissolution testing. The dissolution for each
390 nm. The CMC/Cs/CAC of the mixtures were deter- formulation was conducted in triplicate and the data was
mined by plotting the ratio of fluorescence intensities at collected at an interval of every 15 s. The plots in
374 nm (I1) and 385 nm (I3) vs the concentration of
docusate sodium. (23,25–27).

Analysis of Zeta Potential

Aqueous solutions of povidone, docusate sodium, SLS,

and their combinations were prepared based on their
respective proportions in the formulations as described in
Table I for povidone and docusate sodium, and the concen-
tration of SLS in the dissolution media. Zeta potential
measurements of the samples were conducted in a folded
capillary cell (DTS1060) designed especially for zeta poten-
tial measurements using a Zetasizer, Nano ZS ZEN3600,
(Malvern Instruments, Westborough, MA). During the test,
the velocity of charged particles, commonly referred to as
their electrophoretic mobility (μe), induced due to their
attraction towards the oppositely charged electrode in the
electric field generated by the instrument, is measured. The
zeta potential is calculated using Henry’s equation (25,28):

3η
ζ¼ μ ð1Þ
2εF ðKaÞ e

where ζ is the zeta potential, ℰ is the dielectric constant, F

(Ka) is the Henry’s function, and η is the viscosity. F (Ka)
value of 1.5 was used to calculate zeta potential values from
the electrophoretic mobility.
Fig. 1. Drug release in dissolution media containing 0.5% w/v SLS
from tablets of formulations a F1, F2, and F3; b F4, F5, and F6. Each
point refers to a mean ± SD (n = 3)
 Parikh et al.

corresponding figures have been constructed using limited

data points obtained at an interval of 2.5 min throughout the
duration of the test. Figure 1b shows the extent of drug
release from tablets prepared from formulations F4, F5, and
F6 containing, respectively, 0, 0.025, and 0.075% w/w of
docusate sodium with 5% w/w of povidone. After 20 min,
formulations F4, F5, and F6 released, respectively, 78%, 60%,
and 35% API. At the end of 60 min, nearly complete drug
release, ~ 85% was seen from formulations F4 and F5 while
only 60% drug was found to be released from formulation F6.
Complete drug release was seen from formulation F6 in the
subsequent 15 min of testing which was conducted at a paddle
speed of 250 RPM.
From the dissolution tests conducted in 0.5% w/w SLS
media it was observed that, in general, the extent of drug
release decreased as the proportion of docusate sodium in the
formulations increased, except for formulation F3, where the
extent of drug release was relatively higher at a higher
concentration of docusate sodium (1.4% w/w). Additionally,
by comparing dissolution plots of formulations F1 and F6
which consisted of, respectively, 2.5% and 5% w/w povidone
and same amount of docusate sodium, 0.075% w/w, it was
observed that the rate and extent of drug release decreased
considerably with an increase in the proportion of povidone
in the formulation.
Fig. 2. Drug release in dissolution media containing 2% w/v SLS
from tablets of formulations a F1, F2, and F3; b F4, F5, and F6. Each
Dissolution Tests in 2% w/v SLS Medium point refers to a mean ± SD (n = 3)

The dissolution tests conducted in 0.5% w/v SLS media

demonstrated the impact of the proportion of docusate Fluorescence Spectroscopy
sodium on the extent of drug release from the prepared
formulations. Since it was seen that the rate and extent of CMC of docusate sodium in absence of povidone along
dissolution decreased as the extent of docusate sodium with CAC, Cs, and CMC of docusate sodium in presence of
increased, it was of interest to determine if increasing the 2.5% w/v and 5% w/v of povidone are shown in Fig. 3. CMC of
proportion of surfactant in the dissolution media would have 0.02% w/v was obtained for docusate sodium in absence of
an impact on the rate and extent of drug release from the povidone. At a concentration of 2.5% w/v of povidone, docusate
prepared formulations. Figure 2a, b show the extent of drug sodium exhibited a CAC of 0.0075% w/v, Cs of 0.7% w/v and
release from formulations F1–F6 in dissolution medium CMC of 1.0% w/v. In presence of 5.0% w/v povidone, CAC, Cs,
composed of 2% w/v SLS dissolved in deionized water. and CMC values of 0.002% w/v, 0.7% w/v, and 0.9% w/v
Formulations F1, F2, and F3 exhibited, respectively, 70%,
40%, and 45% drug release while formulations F4, F5, and F6
showed respectively, 75%, 50%, and 35% drug release at the
end of 20 min of testing. At the end of 60-min, formulations
F1 to F5 showed nearly complete drug release, ca. 85%, while
formulation F6 was able to show only 60% release. Complete
recovery (> 90% release) of the API from formulation F6 was
obtained after additional testing at 250 RPM for subsequent
15 min. As seen during the dissolution studies in media
containing 0.5% w/v SLS, the extent of drug release
decreased with an increase in the proportion of docusate
sodium in the tablets with the exception of formulation F3,
which consisted of 1.4% w/w docusate sodium. It was also
seen that the rate and extent of drug release lowered as the
proportion of povidone in the formulations increased. Sur-
prisingly, the rate and extent of dissolution in media
containing 2% w/v SLS was almost identical to the rate and
extent of dissolution in media containing 0.5% w/v SLS Fig. 3. CAC (critical aggregation constant), Cs (concentration of the
indicating that the concentration of SLS had a negligible surfactant at which the polymer chains are completely saturated with
impact on the rate of dissolution and that the dissolution was the surfactant), and CMC (critical micelle concentration) of aqueous
predominantly controlled by the proportion of docusate solutions of docusate sodium in presence of 2.5% w/v or 5% w/v
sodium and povidone in the tablets. povidone
Effect of the Interaction Between an Ionic Surfactant and Polymer

respectively were seen. The CAC of docusate sodium in that the CAC, Cs, and CMC of docusate sodium in presence
presence of PVP was found to be much lower than its inherent of povidone were found to be lower than 1.4% w/v (Fig. 3).
CMC (0.02% w/v in absence of povidone) indicating interaction Above Cs, the polymer surface is saturated by surfactant and
between the two components in aqueous media. further addition of surfactant provides monomers in the
microenvironment of the tablet which leads to increase in
zeta potential as well as rate and extent of drug release by
Determination of Zeta Potential lowering the surface tension. The higher rate and extent of
drug release for formulation F3 in comparison F2 can also be
Zeta potentials of aqueous solutions of docusate sodium, attributed to this phenomenon.
SLS, and povidone along with aqueous solutions of their
binary and ternary mixtures were determined to evaluate
DISCUSSION
potential aggregation/interaction between povidone and the
surfactants by means of change in total surface charge, and to
Docusate sodium is commonly used as a surfactant in
estimate its impact on the rate and extent of drug release
parenteral, topical as well as solid and liquid oral formulations
from the prepared formulations. The composition of the
(3,29,30). Accordingly, it was incorporated in the current
tested aqueous solutions and their corresponding zeta poten-
formulation to enhance the dissolution rate of the API that
tial values are presented in Table II and Fig. 4. Mod values of
inherently exhibits extremely poor aqueous solubility. However,
zeta potential have been used in some sections of the
discussion for ease of understanding. Aqueous solution of
docusate sodium at concentrations of 0.025% w/v, 0.075% w/
v, and 0.213% w/v, showed zeta potential values of – 24 mv, −
43 mv, and – 50 mv respectively. Similarly, aqueous solution
of 0.5% and 2% w/v SLS, which is also an anionic surfactant,
were found to be – 54 mv and − 70 mv. The zeta potential
values for aqueous solutions of povidone were found to be
nearly neutral. Consequently, aqueous solutions of binary
mixtures of docusate sodium and povidone exhibited a
negative zeta potential for all the concentration studied;
however, a considerable drop was seen in the zeta potential
values in comparison to the neat surfactant solutions indicat-
ing potential interaction between docusate sodium and
povidone. The zeta potential values were found to increase
with the increase in concentration of docusate sodium at a
fixed concentration of povidone and decrease with the
increase in concentration of povidone at a given concentra-
tion of docusate sodium. Surprisingly, it was found that the
aqueous solutions of ternary mixtures of povidone, docusate
sodium, and SLS exhibited lower zeta potential values in
presence of 2% w/v SLS in comparison to 0.5% w/v SLS,
indicating possible interaction between the surfactants in
addition to potential aggregation with povidone. It was
observed that the zeta potential values of the aqueous
solutions of the binary or ternary mixtures containing 1.4%
w/v of docusate sodium were considerably higher in compar-
ison to all other tested mixtures. This can be explained by
results from fluorescence spectroscopy where it can be seen

Table II. Zeta Potential Values of Aqueous Solutions of PVP, SLS,

and DS at Various Concentrations. Each Value Refers to a Mean ±
SD (n = 3)

Ingredient (concentration in % w/v) Zeta potential (mv) ± sd

PVP (2.5) 0.22 ± 0.22

PVP (5.0) 0.33 ± 0.03
SLS (0.5) − 53.97 ± 4.63
SLS (2.0) − 70.40 ± 2.26
DS (0.025) − 24.30 ± 2.05
DS (0.075) − 43.03 ± 2.84 Fig. 4. Zeta potential values of aqueous solutions of povidone and
DS (0.213) − 49.53 ± 4.01 docusate sodium at various concentrations in a absence of SLS; b in
presence of 0.5% w/v SLS; and c in presence of 2% w/v SLS
 Parikh et al.

as seen in Figs 1 and 2, incorporation of docusate sodium resulted
in an adverse effect on the rate and extent of drug release from
the prepared formulations irrespective of the concentration of
SLS in the dissolution media (0.5% w/w or 2% w/v SLS) or the
proportion of povidone in the formulations (2.5% or 5% w/w). In
fact, from among the tested formulations, formulation F4, which
did not contain docusate sodium, exhibited the fastest rate of drug
release. In general, the dissolution rate progressively decreased as
the extent of docusate sodium in the formulations increased,
except, in the case of formulation F3 where the rate of drug
release was faster than formulation F2 in spite of the higher
concentration of docusate sodium in the formulation. Addition-
ally, it can be inferred that the rate of drug release decreased as
the proportion of povidone in the formulation increased, which
could be anticipated, since povidone was incorporated as a binder
in the prepared formulations. It was also observed that the
concentration of SLS in the dissolution medium did not have a
significant impact on the rate of drug release from the formula-
tions since the dissolution profiles were almost identical in 0.5%
w/v and 2% w/v SLS dissolution media, i.e., the rate and extent of
dissolution of each of the tested formulations was found to be
nearly identical in spite of a four-fold difference in the concen-
tration of SLS (0.5 vs 2% w/v) in the dissolution media. This
indicates that the interaction between SLS and povidone in the
dissolution media is minimal, if any. On the other hand, a
comparatively nominal change in the proportion of docusate
sodium had a considerable impact on the rate and extent of
dissolution from the formulations. For example, the proportion of
docusate sodium in formulation F1 and F2 was 0.075% and
0.213% w/w respectively. The extent of drug release at the end of
20 min of dissolution in media containing 2% w/v SLS was found
to be 70% and 40%, respectively, for formulation F1 and F2.
Similarly, formulations F4, F5 and F6 consisted of, respectively,
0%, 0.025%, and 0.075% w/w docusate sodium. The extent of
drug release after 20 min in the dissolution media containing 2%
w/v SLS was found to be 75%, 50%, and 35% respectively.
As presented in Table I, the concentration of docusate
sodium ranged from 0 to 1.4% w/w in the tablet formulations
which would correspond to a maximum concentration of
0.0006% w/v in the dissolution media. It is unlikely that the
rate and extent of dissolution would be governed by such low
concentration of surfactant in the bulk of the dissolution
media. This indicates that docusate sodium is responsible for
regulating the rate of drug release by influencing the surface/
microenvironment of the dissolving drug particles rather than
influencing the dissolution process by preferentially dissolving
in the bulk of the dissolution media.
The decrease in the rate of drug release can thus be
attributed to the interaction between povidone and docusate
sodium at the interface of the dissolving drug particles during
dissolution. As described earlier, during dissolution in aque-
ous media, anionic surfactants can interact with polymeric
components present within the formulation at a certain
concentration of the surfactant (CAC), wherein small surfac-
tant clusters adsorb on to polymer chains to form aggregates.
The aggregation would be dependent on the proportion of
docusate sodium in the formulation as the size of the clusters
would increase with the surfactant concentration and the
number of binding sites will increase with polymer concen-
tration. At high concentration of surfactant, formation of
intermolecular network between the surfactant clusters and
polymer chains leads to a further increase in the viscosity of
the solution in the microenvironment of dissolving particles.
This would lead to an increase in the diffusion path length
and retard the diffusion of the drug thus decreasing the rate
of drug release. This phenomenon has been depicted in Fig. 5.
Gebrehemskel et al. reported a similar effect of docusate
sodium on the rate of drug release from solid dispersion of a
poorly soluble API prepared with polyvinylpyrrolidone K-30
(22). The rate of drug release was higher than crystalline API;
however, it was considerably lower than the API-PVP K-30
solid dispersion without docusate sodium, with a difference of
almost 40% at certain time points during the test.
In the current studies, the CAC, Cs, and CMC of docusate
sodium in presence of povidone were determined by fluorescence
spectroscopy. The I1/I3 ratio of pyrene varies with the polarity of its

Fig. 5. Depiction of the effect of polymer and surfactant concentration and their interaction on the surface/interfacial tension of the dissolving
drug particles. As the concentration of the surfactant in the formulation increases the strength of the interaction between the surfactant and
polymer also increases leading to formation of an intermolecular network between the polymer chains and therefore an increase in the viscosity
of the microenvironment of the dissolving particles. CAC: critical aggregation constant; Cs: concentration of the surfactant at which the
polymer chains are completely saturated with the surfactant; CMC, critical micelle concentration
Effect of the Interaction Between an Ionic Surfactant and Polymer
environment. The ratio is high in a polar environment. As the
surfactant concentration increases the ratio rapidly decreases and
above CMC it reaches a constant indicating incorporation of
pyrene into hydrophobic micellar environment (31). The CMC of
docusate sodium in absence of PVP is inherently low (0.02% w/v).
It has been shown that in presence of surfactant, the CAC of ionic
surfactants can be much lower than their CMCs. For example, Qi
et al. showed that the CAC of SDS was much lower than its CMC
in the presence of HPMC. Martins and Deshpande showed a
similar phenomenon for SLS in presence of HPC (20) and various
other polymers (23). In the current studies it was observed that in
presence of povidone the CAC of docusate sodium was at a much
lower concentration than its inherent CMC. Following initial
decrease in I1/I3 ratio indicating CAC, the Cs was indicated by
an increase in the I1/I3 ratio followed by another rapid decrease in
intensity ratio and then plateau indicating CMC. The results
confirm the aggregation of docusate sodium with povidone which
further explains the impact of the presence of docusate sodium on
rate and extent of drug release from these formulations.
In order to verify the aggregation of docusate sodium and
povidone in aqueous media, zeta potential values of the mixtures of
docusate sodium, povidone, and SLS were measured. It can be
observed that the zeta potential values of aqueous solutions
containing surfactants and povidone were considerably lower than
the zeta potential values of solutions of neat surfactants. This is
indicative of the adsorption of surfactant monomers on the surface
of the polymer or surfactant polymer agglomeration. The zeta
potential values of solutions containing docusate sodium and
povidone gradually increase with an increase in the concentration
of docusate sodium irrespective of the concentration of povidone.
Moreover, zeta potential values are higher in solutions containing
2.5% w/v of povidone in comparison to 5% w/v povidone
irrespective of the concentration of docusate sodium in the solution.
A lower zeta potential value at higher concentrations of the
polymer would be the result of the limited extent of free surfactant
monomers in the solution due to higher amount of surfactant
required for polymer surface coverage. Similar observations were
noted for the mixtures containing SLS, docusate sodium, and
povidone. Solutions containing 0.5% w/v of SLS exhibited higher
zeta potential values than those without SLS irrespective of the
concentration of povidone and docusate sodium. However,
solutions containing 2.0% w/v of SLS exhibited zeta potential
values comparable to those without SLS up to 0.7% w/v of
docusate sodium (data not shown). Lower zeta potential values in
presence of 2% w/v SLS in comparison to 0.5% SLS could be a
result of higher ionic strength of the resultant solutions due to the
ionization of the SLS and thus a reduction in the size of the electric
double layer around the particles (32). Nevertheless, although of a
low magnitude in comparison to neat surfactant, a higher zeta
potential value indicates the presence of higher number of free
monomers. The presence of free monomers would lead to a
reduction in the surface tension. The surface tension would thus
lower with an increase in the concentration of docusate sodium
resulting in faster rate of drug release. However, the contradicting
drug release behavior, i.e., a slower drug release in presence of a
higher concentration of surfactant indicates that a minor increase in
the zeta potential may not be sufficient to lower the surface tension
significantly. Therefore, it can be concluded that the drug release in
this system is governed by the interaction between the polymer and
surfactant in the formulation during dissolution. Furthermore,
although lower zeta potential values were observed for ternary
mixtures containing 2% w/v SLS in comparison to 0.5% w/v, no
significant differences in dissolution profiles for each of the
formulations at either of the explored concentrations of SLS
also indicate that the drug release is governed by interaction
between docusate sodium and povidone.
Nilsson et al. showed that as the concentration of polymer
and surfactant increases, there is a proportional increase in the
size of the polymer-surfactant clusters, and at high concentrations
of the polymer, an intermolecular network is formed between the
clusters leading to an increase in the viscosity of the solution (15).
Upon complete saturation of the polymer any additional
surfactant monomers would be available to enhance the dissolu-
tion rate of the drug, and at a certain concentration of the
surfactant (CMC), the monomers would associate to form
micelles. Consequently, the zeta potential of the solution is
expected to rise as the concentration of free monomers or
micelles increases. In the current studies, a higher rate of drug
release from formulation F3, in comparison to formulation F2,
can be attributed to the availability of excess free surfactant
monomers beyond complete saturation of the polymer chains by
the surfactant resulting in lower interfacial tension of the
dissolving drug particles or to the loss of polymer network leading
to a decrease in the viscosity of the microenvironment of the
dissolving particles.
CONCLUSION
Use of surfactants in formulations is proven to enhance
the dissolution rate of poorly water soluble drugs. The rate
and extent of dissolution is expected to increase with an
increase in the proportion of the surfactant; however, the rate
of drug release was found to decrease as the proportion of
anionic surfactant, docusate sodium, in the formulation
increased. The decrease in the rate of release was attributed
to an increase in the viscosity of the microenvironment of
dissolving particles caused by interaction of the ionic surfac-
tant with the polymeric binder (povidone) in the aqueous
media during dissolution. Therefore, in addition to binary
drug excipient compatibility studies, prudent evaluation of
the interaction of ionic surfactants with polymeric components
within the formulation is necessary to ensure the selection of
an appropriate type and concentration of the surfactant, and
consequently, to avoid unexpected impediments in the
development process.
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