Research Paper

Atypical effects of incorporated surfactants on stability and

dissolution properties of amorphous polymeric dispersions
Hisham Al-Obaidia, M. Jayne Lawrenceb and Graham Bucktonc
a
The School of Pharmacy, University of Reading, Reading, bInstitute of Pharmaceutical Science, King’s College London and cThe School of
Pharmacy, University College London, London, UK

Keywords Abstract
dissolution rate; glass transition
temperature; globules; solid dispersions; Objectives To understand the impact of ionic and non-ionic surfactants on the
spray drying; surfactants dissolution and stability properties of amorphous polymeric dispersions using
griseofulvin (GF) as a model for poorly soluble drugs.
Correspondence
Methods Solid dispersions of the poorly water-soluble drug, griseofulvin (GF)
Hisham Al-Obaidi, The School of Pharmacy,
University of Reading, Reading RG6 6AD,
and the polymers, poly(vinylpyrrolidone) (PVP) and poly(2-hydroxypropyl
UK. methacrylate) (PHPMA), have been prepared by spray drying and bead milling
E-mail: h.al-obaidi@reading.ac.uk and the effect of the ionic and non-ionic surfactants, namely sodium dodecyl
sulphate (SDS) and Tween-80, on the physico-chemical properties of the solid
Received May 3, 2016 dispersions studied.
Accepted August 24, 2016 Key findings The X-ray powder diffraction data and hot-stage microscopy
showed a fast re-crystallisation of GF. While dynamic vapour sorption (DVS)
doi: 10.1111/jphp.12645
measurements indicated an increased water uptake, slow dissolution rates were
observed for the solid dispersions incorporating surfactants. The order by which
surfactants free dispersions were prepared seemed critical as indicated by DVS
and thermal analysis. Dispersions prepared by milling with SDS showed signifi-
cantly better stability than spray-dried dispersions (drug remained amorphous
for more than 6 months) as well as improved dissolution profile.
Conclusions We suggest that surfactants can hinder the dissolution by promot-
ing aggregation of polymeric chains, however that effect depends mainly on how
the particles were prepared.

may also be beneficial in helping to understand whether

Introduction
Surfactants are widely used to improve the dissolution rate
and aqueous solubility of poorly water-soluble drugs.[1,2]
As a consequence, it may be anticipated that if a surfactant
is incorporated into a solid dispersion of amorphous drug,
it would be possible to further enhance the dissolution rate
of the poorly water-soluble drug. The impact of surfactants
on release properties has been reviewed where the role of
surfactant has been shown positive on the release kinetics
of hydrophobic drugs.[3] For example, dissolution of oflox-
acin was significantly improved when was incorporated
with polyethylene glycol and Tween-20 solid dispersions.[4]
In another study, incorporation of Tween-80 into flur-
biprofen and sodium carboxymethyl cellulose resulted in
~60-fold improvement in aqueous solubility.[5] The influ-
ence of surfactant on a solid dispersion of amorphous drug
bile salts, naturally occurring surfactants present in the gas-
trointestinal tract, can favourably influence the dissolution
of amorphous drugs. In this context, it was recently found
that bile salts incorporated into solid dispersions could
improve dissolution of pravastatin in the gastrointestinal
tract.[6]
However, it is well established that a number of factors
can influence the properties of solid dispersions.[7–9] These
variables are thought to affect the non-covalent interactions
between the drug and polymers used and thereby influence
dissolution rate. For example, we have shown that the sol-
vent used for spray drying can have a significant effect on
properties of the resulting solid dispersion[9] with solid dis-
persions prepared using the same ratio of drug : polymer
but using solvents possessing completely different physical
properties. These differences were attributed to the

© 2016 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2016), pp. **–** 1
Atypical effects of incorporated surfactants
differing molecular interactions between the drug and poly-
mer molecules in the various solvents. In a recent study,
stability of amorphous indomethacin and solubility in
supersaturated suspensions was found to depend on the
polymer and method of incorporation.[10]
It is therefore reasonable to suggest that surfactants,
like polymers, may have an impact on the intermolecular
interactions present in solid dispersions. Incorporation of
surfactants can be very different depending on whether
the drug and polymer solid dispersion were prepared by
spray drying from solution or by mixing as solids as in
bead milling; in this case, the presence of surfactant may
also aid in the dissolution of drug in the solid disper-
sion. Consequently, comparison of the method of prepa-
ration with the solid dispersions being prepared by spray
drying or bead milling will be studied in this study. This
is a continuation to our previous work which showed
significant differences in the properties of formed solid
dispersions when solvents were changed,[9] in an attempt
to understand mechanisms of solid dispersion formation.
While a negative impact for Tween-80 and SDS on, for
example, dissolution of carbamazepine–nicotinamide
cocrystals was previously reported,[11] this study was to
our knowledge the first to report significant variation in
physical properties due to methods used to prepare the
dispersions.
To investigate the influence of addition of surfactants on
solid dispersions prepared by either spray drying or bead
milling, solid dispersions of the poorly water-soluble drug
griseofulvin (GF) were prepared. We have previously
shown that ternary solid dispersions of GF with poly(2-
hydroxypropyl methacrylate) (PHPMA) and poly(vinyl
pyrrolidone) (PVP) allowed the GF to remain in the amor-
phous form for extended periods.[9,12] In this study, the
effect of surfactants (namely Tween-80 (non-ionic surfac-
tant) and SDS (anionic surfactant) on the properties of
solid dispersions is studied. These surfactants were selected
as they are very commonly used pharmaceutical surfactants
and represent examples of charged and non-charged surfac-
tants, which may be significant in terms of their effect on
the interactions in the solid dispersion. They also vary in
terms of their aggregation number and critical micellar
concentration which can affect the properties of the formed
solid dispersion.
Materials and Methods
Materials
Griseofulvin, polyvinylpyrrolidone (PVP) (molecular
weight = 55 000 Da) and Tween-80 were purchased from
(Sigma, Dorset, UK). Poly[N-(2-hydroxypropyl)methacry-
late] (PHPMA) (molecular weight = 20 000 Da) and
2 © 2016 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2016), pp. **–**
Hisham Al-Obaidi et al.
sodium dodecyl sulphate (SDS) were obtained from Fisher.
Acetone was supplied by BDH. All chemicals were of the
highest grade possible and used directly without further
purification.
Methods
Preparation of solid dispersions: spray drying
method
Griseofulvin (2.5 g) was added to a conical flask containing
acetone (185 ml), and the resulting mixture stirred for at
least 3 min until the solid GF was completely dissolved.
Distilled water (85 ml) was then poured into this solution
followed by the addition of PHPMA (1.25 g). The resulting
mixture was stirred for 30–45 min to ensure complete dis-
solution after which time PVP (1.25 g) was added and the
solution stirred for a further 5 min to completely dissolved
the PVP. To examine the effect of the different surfactants
on the resulting solid dispersions, sufficient SDS or Tween-
80 was added to produce a final SDS concentration of 0.05,
0.1, 0.2, 0.5 or 1 w/w% or a final Tween-80 concentration
of 0.1, 0.2, 0.5, 1 and 5 w/w%. The resulting solution was
then spray-dried using a Niro Micro Spray Drier (Niro,
Soeborg, Denmark) inlet temperature of 65 °C, outlet tem-
perature of 45 °C, chamber gas flow of 25 kg/h and atomi-
ser gas flow of 2.5 kg/h.
Preparation of solid dispersions: bead milling
Different ratios were selected of GF, PHPMA, PVP with 1%
SDS in the range of 10–50% GF with equal amounts of
PHPMA and PVP; for example, 50% GF was mixed with
25% PVP and 25% PHPMA and 1% SDS. Solids (2 g) were
loaded into a zirconium jar and milled using 10-mm zirco-
nium beads using Fritsch Pulverisette five planetary mill
(Fritsch, Idar-Oberstein, Germany) for 24 h at a rotary
milling speed of 300 rpm to ensure conversion of the drug
to the amorphous state. The bead milled solid dispersions
were then sieved using a 90-lm sieve and stored at room
temperature in a desiccator under vacuum, over phospho-
rus pentoxide (P2O5) to maintain 0% RH.
Dynamic vapour sorption
Solid dispersions of GF (10 mg) were weighed at 25 °C
using a dynamic vapour sorption analyser (SMS, London,
UK). The RH of the solid dispersion was then adjusted
using nitrogen as carrier gas where one line of gas had a
RH of 100% and the second line a RH of 0%. By mixing
various amount of gas from both lines, it was possible to
obtain the desired RH, which was determined using tem-
perature and humidity probes.
Hisham Al-Obaidi et al.
Hot-stage microscopy
Hot-stage microscopy (HSM) was performed using Zeiss
LSM 510 Meta (Zeiss, Oberkochen, Germany), equipped
with three lasers, namely a 30 mW Argon ion laser (spectral
lines of 458, 477, 488 (blue line) and 514 nm), a 1 mW
HeNe laser (543 nm (green line)) and a 5 mW HeNe laser
(633 nm (red line)). Suspending medium was added drop
wise to a slide and heated at 2 °C/min from room tempera-
ture to 37 °C at which temperature was maintained. Solid
dispersions were then added at the side of the slides with
the minimum amount of agitation and any subsequent
changes recorded.
Scanning electron microscopy
Scanning electron microscopy (SEM) was performed using
a Philips/FEI KL (Philips, Eindhoven, Netherlands). The
sample of solid dispersion was first fixed on an aluminium
stub using conductive double-sided carbon adhesive tape
and the samples sputter coated with gold for 3 min at
30 mA (Emitech K550; Ashford, Kent, England).
X-ray powder diffraction
X-ray powder diffraction (XRPD) was performed on the
solid dispersions at ambient temperature using a Philips X-
ray powder diffractometer (Philips, Cambridge, UK) fitted
was CuKa radiation at 30 mA and 45 kV. Before measure-
ment, the samples were stored at room temperature in a
desiccator containing an excess amount of KCl to achieve a
RH of 85%. The samples were scanned at 0.5°/min and
over diffraction angles (2h) of 5–35°.
Differential scanning calorimetry
The glass transition temperature and heat of recovery were
measured using Perkin-Elmer Pyris 1 (Perkin-Elmer, Wal-
tham, MA, USA). Solid dispersion (5–10 mg) was weighed
into aluminium pans which were then hermitically crimped
using a lid containing pin holes. Any residual solvent con-
tained in the solid dispersion was first removed by increas-
ing the temperature of the instrument to 90 °C and
holding at this temperature for 10 min. The pans contain-
ing the solid dispersion were then cooled to 30 °C and
heated to 180 °C using a heating rate was 10 °C/min. Glass
transition temperature was measured by reheating the sam-
ple over the entire region from 25 to 180 °C. To measure
heat of recovery, the thermal history was removed by heat-
ing the sample above the glass transition temperature
(105 °C) and the temperature was held for 10 min. The
samples were then annealed at 60 °C for different time
periods (3, 6 and 15), and then, the heat of recovery was
© 2016 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2016), pp. **–**
Atypical effects of incorporated surfactants
measured using the step-scan mode. The non-reversible
part of the curve was separated to calculate the heat of
recovery using scanning rate of 10 °C/min, a step change of
2 °C and an isothermal time of 0.5 min (Pyris 1 DSC;
Perkin-Elmer, Beaconsfield, UK).
Dissolution studies
A Pharma Test dissolution apparatus (Pharma Test, Hain-
burg, Germany), connected to a Cecil UV–Vis spectropho-
tometer (Cecil CE 2020; Cecil Instruments, Cambridge,
UK), was used to measure dissolution of GF from the solid
dispersions in 900 ml of phosphate buffer at pH 6.8 and at
37 °C. The paddles were set at 25  2 mm from the bot-
tom of the dissolution vessel to ensure they met BP specifi-
cations and rotated at 100 rpm. Aliquots of dissolution
media were taken at 10–20 min intervals from each vessel
and filtered through 0.45-lm disposable filter units (Darm-
stadt, Germany). The absorbance of the filtered aliquots
was measured at 294 nm. To maintain sink conditions,
amount of GF was kept within 10–15% of saturated aque-
ous solubility following similar reported method.[9]
Data analysis
Data analysis was performed using variety of tests to com-
pare different groups as well as individual sets of data. Dif-
ferences between mean values were analysed using one-way
analysis of variance (ANOVA) followed by a Dunnett’s post
hoc test as well as nonparametric two-tailed test as Mann–
Whitney U or Kruskal–Wallis test as appropriate (SPSS
software v22; IBM, New York, USA). P-values less than
0.05 were considered significant for all statistical tests.
Results
Crystallinity content
The solid dispersions were examined using XRPD to
determine any polymorphic changes occurred in the GF
using the different processing conditions. Previously,
we have shown that solid dispersions of 2 : 1 : 1
GF : PHPMA : PVP prepared in the same way but in the
absence of surfactant remained amorphous when stored
under a high relative humidity of 85% for more than
4 months.[12] In contrast, in this study, the same solid dis-
persions containing either SDS or Tween-80 exhibited a
high crystalline content (Figures 1 and 2) with the crys-
talline content of the solid dispersions being found to be
proportional to the amount of surfactant present. Further-
more, crystallisation was observed to occur quickly fast as
dispersions with 1% SDS content showed clear evidence of
crystallisation after 7 days of storage (Figure 3).
3
Atypical effects of incorporated surfactants Hisham Al-Obaidi et al.

Figure 1 X-ray powder diffraction pattern of spray-dried solid dispersions of GF : PHPMA : PVP (2 : 1 : 1 by weight) containing different ratios
of SDS after 4 months storage at 85% RH and at room temperature. GF, griseofulvin; PHPMA, poly(2-hydroxypropyl methacrylate); PVP, poly(vinyl
pyrrolidone).

Figure 2 X-ray powder diffraction pattern of spray-dried solid dispersions of GF : PHPMA : PVP (2 : 1 : 1 by weight) containing different ratios
of Tween-80 after 4 months storage at 85% RH and at room temperature. GF, griseofulvin; PHPMA, poly(2-hydroxypropyl methacrylate); PVP,
poly(vinyl pyrrolidone).

promote crystallisation in Tween-80 solid dispersion (Fig-

Dynamic vapour sorption studies
As can be seen in (Figure 4), solid dispersion containing
SDS showed significant water uptake compared to surfac-
tant free dispersion. This could be due to differences in the
surface energy and relaxation of the amorphous material at
the surface.[8,13] It was found recently that structural relax-
ation at the surface can significantly differ from relaxation
in the bulk of amorphous particles.[8] Localisation of the
surfactant at the surface of the particles can therefore affect
the relaxation energy and eventually the crystallisation rate.
As shown below, the glass transition temperature decreased
which could suggest annealing effect when surfactants were
incorporated. Using even lower RH (30%) was sufficient to
ure 5). This, however, requires further investigation to con-
firm localisation of surfactants within prepared particles.
We showed previously that changing solvents can cause
dramatic effects on resulting spray-dried particles, where it
was found that rate of evaporation can be distinctively dif-
ferent.[9] In the current study, same solvents were used but
with surfactants added, and therefore, properties such as
solubility in residual solvent can change. As both GF and
PVP contain hydrogen bond acceptor, groups then the
order by which these molecules are added to PHPMA (hy-
drogen bond donor) might be critical. Solid dispersions
were therefore prepared by first dissolving GF in the sol-
vent, followed by PHPMA and finally PVP. Additionally,

4 © 2016 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2016), pp. **–**
Hisham Al-Obaidi et al. Atypical effects of incorporated surfactants

Figure 3 X-ray powder diffraction pattern of spray-dried solid dispersions of GF: PHPMA: PVP (2 : 1 : 1 by weight) containing 1% SDS after
7 days storage at 85% RH and at room temperature. GF, griseofulvin; PHPMA, poly(2-hydroxypropyl methacrylate); PVP, poly(vinyl pyrrolidone).

Figure 4 Dynamic vapour sorption isotherms of spray-dried solid dispersions of GF : PHPMA : PVP (2 : 1 : 1 by weight) containing 1% SDS
using a drying cycle of 0% RH followed by 95% RH and a final drying cycle at 0% RH. GF, griseofulvin; PHPMA, poly(2-hydroxypropyl methacry-
late); PVP, poly(vinyl pyrrolidone).

solid dispersions were prepared where PHPMA was added
to the mixture either first or last. The resulting solid disper-
sions were prepared by spray drying using the same condi-
tions.
As can be seen in (Figure 6), the amount of water uptake
was greater for the solid dispersions prepared by adding
PHPMA to the mixture last compared to the other orders
of addition. This can be clearly seen by examining the per-
centage change in mass of the sample during the time of
experiment. Crystallisation was evident (as drop in mass at
~420 min and lower base line in the second cycle) in dis-
persions prepared via adding GF then PVP then PHPMA
signifying possible weaker H-bonds formed. Both other dis-
persions used showed no sign of crystallisation. While the
impact of changing the order may diminish when surfac-
tants are added, the mechanism for altered water uptake
could be due to same mechanism, that is altered solubility
in residual aqueous solvent upon spray drying.
Molecular mobility
The glass transition temperature of amorphous materials is
correlated with its molecular mobility.[14] When an amor-
phous drug is present above its glass transition tempera-
ture, then its molecular mobility is expected to be high
resulting in a greater probability of drug crystallisation.[15]
As can be seen in (Figure 7), the glass transition tempera-
ture of amorphous GF decreased from ~81 to ~78.5 °C
when the amount of Tween-80 present in the solid disper-
sion increased from 0.5% to 5%. Significantly, this was a
very small decrease in glass transition temperature, despite
that the 10-fold increase in the amount of Tween-80

© 2016 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2016), pp. **–** 5
Atypical effects of incorporated surfactants Hisham Al-Obaidi et al.

Figure 5 Dynamic vapour sorption isotherms of spray-dried solid dispersions of GF : PHPMA : PVP (2 : 1 : 1 by weight) containing 1% Tween-
80 using a drying cycle of 0% RH followed by 30% RH and a final drying cycle at 0% RH. Sample shows signs of crystallisation. GF, griseofulvin;
PHPMA, poly(2-hydroxypropyl methacrylate); PVP, poly(vinyl pyrrolidone).

Figure 6 Dynamic vapour sorption isotherm of GF : PHPMA : PVP spray-dried solid dispersion prepared using different order of adding the solids
into solution using drying cycle at 0% RH followed by 85% RH and a final drying cycle at 0% RH. Particles prepared via adding GF then PVP and
then PHPMA crystallised at 420 min exposure, differences considered significant at P < 0.05. GF, griseofulvin; PHPMA, poly(2-hydroxypropyl
methacrylate); PVP, poly(vinyl pyrrolidone).

present. However, there were some changes observed in the
heat capacity, which could correlate with the enthalpic
relaxation of the amorphous material. Interestingly, evener
smaller changes in the glass transition temperature of GF
were observed for the solid dispersions prepared with SDS
(data not shown). Heat of recovery which can be used as a
direct reflection of molecular mobility was used to measure
relaxation of the dispersions that were prepared using dif-
ferent order of additions (no surfactant) in line with DVS
studies shown above.[16,17] Increased sorbed water can
increase molecular mobility as well as crystallisation
time.[18] As can be seen (Figure 8), the heat of recovery was
highest for GF-PVP-PHPMA indicating highest molecular
mobility. The difference was statistically different after
annealing times of 15 h, while insignificant differences were
found at shorter times. Overall, it was clear that altering the
order of addition resulted in different compositions which
agreed with the DVS observations.
Dissolution experiments
To understand how the molecular interactions in the solid
dispersions affect GF solubility upon exposure water, disso-
lution experiments were performed. Of particular interest
was whether the incorporation of surfactants into the solid
dispersions affects the wettability and apparent solubility of
GF. The results showed that the dissolution rate of GF
decreased when surfactants were incorporated in the solid
dispersion, with the effect being more significant when 5%
Tween-80 was present (statistically different at P < 0.05).
Here, the amount of GF released from the solid dispersion
did not exceed ~40% (Figure 9). When 1% SDS was

6 © 2016 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2016), pp. **–**
Hisham Al-Obaidi et al. Atypical effects of incorporated surfactants

Figure 7 DSC scans showing Tg of spray-dried solid dispersions of GF : PHPMA : PVP (2 : 1 : 1 by weight) containing different amounts of
Tween-80. GF, griseofulvin; PHPMA, poly(2-hydroxypropyl methacrylate); PVP, poly(vinyl pyrrolidone).

Figure 8 Enthalpies of recovery for spray-dried solid dispersions of GF : PHPMA : PVP (2 : 1 : 1 by weight) prepared using different order of
addition annealed at 60 °C, differences considered significant at P < 0.05. GF, griseofulvin; PHPMA, poly(2-hydroxypropyl methacrylate); PVP, poly
(vinyl pyrrolidone).

present, released GF did not exceed ~55%. This result con-
tradicts previous studies; in one study, the aqueous solubil-
ity of valsartan has significantly improved when SDS was
incorporated with HMPC-based solid dispersion.[19]
Interestingly, when 0.2% SDS was added to the dissolu-
tion media to enhance dissolution and wettability of the
particles, similar trends were seen where the SDS-
containing solid dispersions dissolved slower (Figure 9).
There was a correlation between the amount of the surfac-
tant and the dissolution as can be clearly seen in SDS-con-
taining solid dispersions. Slowest dissolution occurred
from dispersions that contained largest ratio of the surfac-
tants and vice versa. Similar trends were seen for Tween-80
dispersions.

© 2016 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2016), pp. **–** 7
Atypical effects of incorporated surfactants Hisham Al-Obaidi et al.

Figure 9 Dissolution profile of (a) GF : PHPMA : PVP spray-dried solid dispersions containing 1% SDS and 5% Tween-80 in pH6.8 phosphate
buffer and at 37 °C and 100 rpm and (b) GF : PHPMA : PVP spray-dried solid dispersion with 1% SDS in pH6.8 phosphate buffer (contains 0.2%
SDS) and at 37 °C and 100 rpm, differences considered significant at P < 0.05. GF, griseofulvin; PHPMA, poly(2-hydroxypropyl methacrylate); PVP,
poly(vinyl pyrrolidone).

The dissolution behaviour of the spray-dried particles
was further investigated using hot-stage microscopy which
allows observing the particles as they dissolve at 37 °C. As
can be seen in (Figure 10), the dissolution of the particles
resulted in almost immediate crystallisation of the drug.
Interestingly, SDS-containing particles showed threads of
particles spontaneously forming when the particles exposed
to water. We expect these lines formed due to the presence
of charge at the surface of the particles. Faster crystallisa-
tion seemed to occur with particles that contained Tween-
80 where needle-shaped crystals could be observed (Fig-
ure 10). It is worth mentioning that despite the presence of
charge in SDS-containing particles, these did not help with
the dissolution of the entrapped drug. The shape of the
particles, however, seemed very different where SDS parti-
cles were smooth spheres, while Tween-80 particles were
irregular in shape as seen in the SEM images (Figure 11).
Although both surfactants containing particles were com-
parable in size, the localisation of the surfactant within the
solid particle might be different depending on the nature of
the surfactant. Hence, differences in dissolution are not
attributed to differences in size of the particles. However,
irregular shaped particles were reported to exhibit slower
dissolution rate due to increase in the average hydrody-
namic boundary layer thickness affecting diffusion of dis-
solved drug.[20] It is not clear whether this shape change
was the main factor for the observed differences in dissolu-
tion.

8 © 2016 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2016), pp. **–**
Hisham Al-Obaidi et al.
Figure 10 Hot-stage microscopy images showing (a) GF : PHPMA : PVP
spray-dried solid dispersion with 5% Tween-80 and (b) GF : PHPMA : PVP
spray-dried solid dispersion with 1% SDS at 37 °C using phosphate buffer
(pH 6.8). GF, griseofulvin; PHPMA, poly(2-hydroxypropyl methacrylate);
PVP, poly(vinyl pyrrolidone).
Discussion
Some physical properties of the formed particles were
expected such as increased rate of crystallisation. This could
be attributed to higher affinity to water that could act as
plasticiser. Unexpectedly, however, it is interesting to
observe that dissolution profile has been negatively affected
by the presence of surfactants. While immediate crystallisa-
tion could be the reason (as shown in hot-stage micro-
scopy), the presence of surfactants should in principle
facilitate water permeation and improve wettability. There
was no evidence for significant increase in molecular
mobility as reflected by slight changes in the glass transition
temperature. The impact of surfactant is therefore believed
to be due to molecular effects possibly promoting polymer
chain entanglements and polymeric globule formation. The
formed globules (before spray drying) seemed to remain in
the solid state, and therefore, diffusion of the drug is
reduced. This suggests the presence of a memory where
interactions that formed in the liquid state (before spray
drying) remained even after the solid particles have had
formed. This goes in line with previous studies that showed
© 2016 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2016), pp. **–**
Atypical effects of incorporated surfactants
(a)
(b)
Figure 11 Scanning electron micrograph showing microparticles of
(a) GF, PHPMA and PVP (2 : 1 : 1 by weight) + 0.05% SDS solid dis-
persion and (b) GF : PHPMA : PVP (2 : 1 : 1 by weight) + 5% Tween-
80 solid dispersion. GF, griseofulvin; PHPMA, poly(2-hydroxypropyl
methacrylate); PVP, poly(vinyl pyrrolidone).
that the solvent used to dissolve the polymer could have
significant impact on properties of formed particles.[21,22]
The polymer takes up a globular conformation when dis-
solved in a poor solvent while exhibiting an extended con-
formation in a good solvent.[23,24] Indeed, we have shown
previously that replacing water with methanol to spray dry
solid dispersions of GF can lead to dramatic changes into
properties of the solid dispersion,[9] although unexpected
but changing the order of adding the polymers and drug
seemed to result in particles with different properties.
It was shown before that evaporation of SDS solution
exhibited lower contact angle with hydrophobic surfaces
indicating enhanced association at the surface.[25] Mean-
while, evaporation rate of SDS solution was found to
marginally deviate from water.[26] Hence, it is expected
that during spray drying, SDS associates with the
hydrophobic tails of PHPMA and that association occurs
in favour of molecular interaction of PHPMA-PVP and
PHPMA-GF. Differences in the shape of SDS and
Tween-80 particles (SEM images) suggest that these
events are controlled by the type of surfactant used. As
9
Atypical effects of incorporated surfactants Hisham Al-Obaidi et al.

Figure 12 The X-ray powder diffraction pattern of GF : PHPMA : PVP (1 : 2 : 2 by weight) + 1% SDS solid dispersion prepared by milling stored
at 85% RH after 6 months from day of preparation. GF, griseofulvin; PHPMA, poly(2-hydroxypropyl methacrylate); PVP, poly(vinyl pyrrolidone).

Figure 13 Dissolution profile of milled solid dispersions of GF : PHPMA : PVP (1 : 2 : 2 by weight) and GF : PHPMA : PVP (1 : 2 : 2 by
weight) + 1% SDS at pH 6.8 and at 37 °C (100 rpm), differences considered significant at P < 0.05. GF, griseofulvin; PHPMA, poly(2-hydroxypro-
pyl methacrylate); PVP, poly(vinyl pyrrolidone).

the HLB for SDS is 40 compared to Tween-80 (HLB
15), it is expected that segregated regions of PHPMA are
localised in the bulk of the particles, while the surface is
occupied by PVP-GF. This assumption may explain dif-
ferent rates for dissolution where SDS-containing surfac-
tants dissolved faster.
To eliminate the effect of solvents and possible surface
association of surfactants, bead milling of GF, PHPMA,
PVP and SDS was used to prepare the solid dispersions. As
shown in (Figure 12), the results showed that milled solid
dispersions remained amorphous for more than 6 months
when stored at 85% RH which contradicts the fast crystalli-
sation observed when the same samples were spray-dried.
Interestingly, the dissolution rate of the particles was faster
(statistically different at P < 0.05) when SDS was incorpo-
rated which suggests totally different structures formed
when the solid dispersions were bead milled (Figure 13).
This agrees with our previous findings where it was found
that milled dispersions showed higher solubility than
spray-dried solid dispersions.[27]
Conclusions
The incorporation of surfactants in solid dispersions
seemed to have significant effect on the properties of the
resulting particles. These effects included altered dissolu-
tion rate, reduced stability, altered interactions between the
drug and the polymer in addition to changes to the mor-
phology of the particles. The mechanism for these effects
seems to depend largely on the method by which the drug
polymer mixtures were prepared. When the particles were
prepared by bead milling, the properties of the particles

10 © 2016 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2016), pp. **–**
Hisham Al-Obaidi et al.
were distinctively different from particles prepared using
spray drying. The presence of surfactants as dissolved in the
liquid state allowed them to localise at the surface of the
particles and that could have promoted aggregation of the
hydrophobic chains of PHPMA.
References
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Declaration
Conflict of interest
The Authors report no conflicts of interest.
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Supporting Information
Additional Supporting Information
may be found in the online version of
this article:
Appendix S1. Details of analytical
analysis using SPSS software.
11