Solubilization Behavior of Poorly Soluble Drugs with
Combined Use of Gelucire 44/14 and Cosolvent
KOHSAKU KAWAKAMI, KYOKO MIYOSHI, YASUO IDA
Developmental Research Laboratories, Shionogi & Co., Ltd., 12-4 Sagisu 5-chome, Fukushima-ku, Osaka 553-0002, Japan
Received 7 October 2003; revised 16 January 2004; accepted 18 January 2004
ABSTRACT: Gelucire 44/14 is a surface-active excipient that can solubilize poorly soluble
drugs. We investigated its solubilization behavior when coexisting with dimethylacetoamide (DMA) or dimethylsulfoxide (DMSO), both of which are also expected to enhance
drug solubility. Gelucire was confirmed to form micelles by surface tension and fluorescence measurements both in water and water/cosolvent mixtures. Light-scattering
measurements revealed that DMA and DMSO affect the micellar morphology in a
different manner. DMA helped form large structures by being entrapped in the
hydrophobic region of the micelles and/or inducing the aggregation. DMSO was likely
to be anchored to the interfacial layer and did not induce micelle growth. Two model
drugs, phenytoin and indomethacin, were employed to observe the solubilization
behavior of poorly soluble drugs in Gelucire/cosolvent mixtures. The solubility of these
drugs in the mixtures could be explained very well by using the new solubility model
introduced in this article. Addition of cosolvents to the Gelucire solution did not enhance
the solubility very much, and thus the combined use of cosolvents with Gelucire offered
only little advantage from the viewpoint of solubility. ß 2004 Wiley-Liss, Inc. and the
American Pharmacists Association J Pharm Sci 93:1471–1479, 2004
Keywords: Gelucire 44/14; dimethylacetoamide;
micelle; solubility; log-linear model; two-phase model
INTRODUCTION
Solubilization of poorly soluble drugs has been a
very important issue in screening studies of
new chemical entities as well as in formulation
research.1,2 As organic cosolvents (this will be
called simply as ‘‘cosolvent’’ hereafter in this
article), dimethylsulfoxide (DMSO) and dimethylacetoamide (DMA), have been widely used3–6
because of their large solubilization capacity for
poorly soluble drugs and their relatively low
toxicity. Gelucire 44/14 has also been recognized
as a powerful solubilization agent.7,8 Therefore,
the combination of Gelucire and cosolvents is
Correspondence to: Kohsaku Kawakami (Telephone: 81 6
6458 5861; Fax: 81 6 6458 0987;
E-mail: kohsaku.kawakami@shionogi.co.jp)
Journal of Pharmaceutical Sciences, Vol. 93, 1471–1479 (2004)
ß 2004 Wiley-Liss, Inc. and the American Pharmacists Association
dimethylsulfoxide;
cosolvent;
commonly employed to solubilize poorly soluble drugs in research of the pharmaceutical
industries.
The solubilization by cosolvents can be expressed by the log-linear model,9–11 that is,
log S ¼ log Sw þ sf ;
ð1Þ
where S and Sw are the solubilities in the
cosolvent–water mixture and water, respectively.
f is the fraction of the cosolvent. s is the solubilization capacity and can be defined by the
following equation using the octanol–water partition coefficient, log P, of the solute.
s ¼ slog P þ t
ð2Þ
Here, s and t are constants that depend only on
nature of the cosolvents. Because these values
have already been provided for ethanol, propylene
glycol, polyethylene glycol 400, and glycerol in
literature,11 all we need to know to predict the
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 93, NO. 6, JUNE 2004
1471
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KAWAKAMI, MIYOSHI, AND IDA
solubility in their water/cosolvent mixtures may
be the log P of the solutes. It has also been shown
that the s value has a strong correlation with log P
for these cosolvents.11 However, this log-linear
model is not applicable, if the solute forms solvate
or the crystal structure is altered by the addition
of the cosolvent.12
The solubilization by surfactants can be described in a simple manner as follows:
S ¼ xðCs Ccmc Þ þ pSw
ð3Þ
Here, x, Cs, and Ccmc are the solubilizing capacity
of micelles, surfactant concentration, and critical
micelle concentration, respectively. p is the coefficient responsible for the change in the bulk
solubility, which is affected by pH change, salting
out, etc., caused by the surfactant. Prediction of
x is difficult, because it greatly depends on the
solubilization site of the drugs in micelles.13 If
the guest drugs are localized deep in the micelles,
x usually increases with increase of the alkyl
chain length.13 It should be noted that eq. 3
ignores the growth of micelles with the surfactant
concentration and structural change by the guest
drug molecules.
It is also difficult to predict how the addition of
cosolvent affects micelle formation, because its
addition significantly change the solution conditions, which affect the interaction between surfactant molecules.14–17 Possible behaviors of the
cosolvent molecules are: (1) increase of surfactant
solubility and inhibition of micelle formation,14,17
(2) action as a cosurfactant and alteration of
micelle characteristics,15 (3) formation of pools
inside micelles, (4) decrease of surfactant solubility and enhancement of micelle formation,14 (5)
existence in the continuum phase with no effect on
micelle formation. This article describes how the
addition of DMSO (or DMA) affects the formation
of Gelucire 44/14 micelles and the solubility of the
drug in the mixture. The effect of using Gelucire in
screening studies in the pharmaceutical industries is also discussed.
An increase in the solubility by the surfactant
frequently makes a much more significant contribution than the cosolvent. Therefore, the solubility
change in the micelles, caused by the addition of
cosolvents, may needed to be considered.
In the model, fraction of surfactant, cosolvent,
and water are defined as fs, fc, and 1 fs fc,
respectively, as shown in Figure 1. The notion of
the partial molar volume is ignored for simplicity.
If the fraction of a of the cosolvent is dissolved in
the continuum phase and the remaining cosolvent
forms the micelle phase with the surfactant, the
fraction of each phase, Fc and Fm, is expressed as
Fm ¼ fs þ ð1 aÞfc
ð5Þ
Fc ¼ 1 fs þ ð1 aÞfc :
ð6Þ
Applying the log-linear model to the solubility of
drug in the micelle phase, the solubility in the
cosolvent, Sc, is written as
Sc ¼ Sw expðsÞ ¼ xexpðs0 Þ;
ð7Þ
where s0 is the solubilization capacity in the
micelle phase. The total solubility of the drug can
be written as
0
S
xFm
s fc ð1 aÞ
safc
¼
exp
þ Fc exp
: ð8Þ
Sw
Fm
Sw
Fc
This equation will be referred to as the twophase model hereafter.
MATERIALS AND METHODS
Materials
Gelucire 44/14 was a gift from Gattefossé (Cedex,
France). It was melted at 608C and mixed well
A SOLUBILITY MODEL FOR COMBINED
USE OF SURFACTANT AND COSOLVENT
If the micelles and cosolvents individually contribute to the solubilization behavior, the resultant solubility Ss may be approximated as
Ss ¼ xCs þ Sw expðsf Þ:
ð4Þ
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 93, NO. 6, JUNE 2004
Figure 1. Schematic presentation of the two-phase
model.
SOLUBILIZATION BEHAVIOR OF POORLY SOLUBLE DRUGS
before use. Indomethacin (IDM), phenytoin (PHT),
pyrene, and dimethylacetoamide (DMA) were
obtained from Wako Pure Chemical Industries
(Osaka, Japan). Dimethylsulfoxide (DMSO) was
supplied from Nacalai Tesque (Kyoto, Japan). All
other reagents were used as supplied.
Surface Tension Measurement
The surface tension of the Gelucire solutions
was measured by the Wilhelmy plate method
using Krüss K12 Surface Tensiometer (Krüss,
Hamburg, Germany). The sample room of the
instrument was maintained at 25 0.28C by
circulating temperature-controlled water. Before
every measurement, the platinum plate was
heated with a burner, followed by rinsing with
distilled water and acetone. Consequently, the
surface tension value was checked with the
surfactant-free solution to confirm the absence of
contamination. All the data were read at 3 min
after the creation of new surfaces. This time
period is too short, if the diffusion of the surfaceactive molecules to the air/liquid surface is very
slow and/or the orientation and the rearrangement of the molecules occur at the surface. These
effects were confirmed not to be significant for
the Gelucire solutions.
Evaluation of Polarity Inside Micelles
The polarity inside the micelles was investigated
using pyrene as a fluorescent probe, because
its fluorescent spectrum greatly depends on the
polarity of its surroundings.17,18 Its spectrum
splits into five sharp peaks, and the most frequently used parameter is the peak ratio of the
first peak and the third peak (I1/I3). The ratio
increases with the increase of the polarity. In the
experiment, pyrene was solubilized at 100 ng/mL
in aqueous solution with the aid of a trace amount
of methanol and subjected to fluorescent measurement (Hitachi F-4010 Fluorescence Spectrophotometer, Tokyo, Japan). The excitation wavelength
was 335 nm and the spectrum was measured from
360 to 400 nm. The first and the third peak were
found around 374 and 384 nm, respectively.
To determine the critical micellar concentration
of Gelucire in each solvent, the I1/I3 values were
examined at various concentrations of Gelucire
with or without 10 w/v% cosolvents. Next, the I1/I3
values of the 5 w/v% Gelucire solutions were
measured at various cosolvent concentrations to
observe the polarity change inside the micelles
1473
after addition of the cosolvent. All the measurements were done with the room temperature controlled at around 258C.
Light-Scattering Measurement
The increase in the micelle size was evaluated by
laser light scattering measurements on Coulter
N4 Plus equipped with He-Ne laser light (Coulter
Corp., FL) at the scattering angle 908. Under
the same instrumental condition, the scattering
intensity I can be written as
2
2
n 1
6
;
ð9Þ
I/R c 2
n þ2
where R, c, and n are the particle radius, particle
concentration, and the relative refractive index
between the particles and the continuum phase,
respectively; 7.5 or 15 w/v% aqueous Gelucire
solutions mixed with various amounts of DMSO
or DMA were assessed in this experiment. All the
measurements were done with the room temperature controlled at around 258C.
Solubility Measurement
Gelucire solutions were prepared by dissolving
an adequate amount in water or the cosolvent
solutions. An excess amount of PHT or IDM was
loaded in a 1-mL centrifuge tube, to which 1 mL of
the solvent was introduced. The tubes were rotated at 50 rpm in a temperature-controlled room
at 258C for 24 h, followed by centrifugation at
1000 rpm for 2 min. The supernatants were diluted with acetonitrile and filtrated using syringe
filters of 450-nm pore size in preparation for
HPLC analysis. PHT concentration was measured using YMC-pack ODS-AM-302 (150 mmL 4.6 mm i.d., YMC Co., Kyoto, Japan) with a flow
rate at 1 mL/min. The mobile phase was 0.2 vol %
acetic acid/acetonitrile ¼ 65/35. The detection
wavelength and the injection volume were
240 nm and 15 mL, respectively. IDM was measured on the same column and the injection
volume. The mobile phase and the detection
wavelength were 0.1 vol % trifluoroacetic acid/
acetonitrile ¼ 40/60 and 320 nm, respectively.
RESULTS
Micelle Formation of Gelucire Solutions
Figure 2 shows the surface tension of the Gelucire
solution with or without 10 w/v% cosolvents. The
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 93, NO. 6, JUNE 2004
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KAWAKAMI, MIYOSHI, AND IDA
Figure 2. Surface tension measurements of the Gelucire solutions. The solvent was water (circles), 10%
DMSO aqueous solution (triangles), or 10% DMA
aqueous solution (squares).
surface tension of the aqueous solution decreased
with increase of the Gelucire concentration.
Although this figure indicates the micelle formation of the Gelucire molecules, the critical micellar concentration (cmc) was difficult to determine
precisely, most likely because Gelucire consists
of many components. Nevertheless, it is clear
that addition of the cosolvents shifted the cmc to
higher concentrations. This trend was more
clearly shown by the fluorescent measurement
as can be seen in Figure 3. The polarity around
pyrene molecules started to decrease around 2 mg/
mL for the aqueous Gelucire solution, indicating
the formation of micelles. The cmc is usually
Figure 3. Fluorescent measurement of the Gelucire
solutions. I1/I3 is the intensity ratio of the first and the
third fluorescent peaks of pyrene (see text). The symbols
are the same as those for Figure 1.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 93, NO. 6, JUNE 2004
taken as the concentration where the intensity
ratio stops to decrease.17 However, because the
observed intensity ratio reflects averaged polarity
between bulk and the micellar phases, the middle
point has been used for surfactants with low
cmc values (below 1 mM).17 In the case of
Gelucire, the cmc value seems to be much lower
than this. Comparison with the fluorescent data
with the surface tension experiments suggests
that the surfactant concentration where the
intensity ratio starts to decrease seems to be the
best choice for deciding cmc values. The cmc
values of Gelucire increased to 8 mg/mL for DMSO
solution and 30 mg/mL for DMA solution. These
were expected results, because the monomer concentration of Gelucire should increase by addition
of the cosolvents.
Figure 4 shows the change in the light-scattering intensity of Gelucire solutions with addition of
the cosolvents. As can be clearly seen, the scattering intensity increased dramatically with the
addition of DMA but not with DMSO. This drastic
increase can be explained by the increase of micelle
size according to eq. 4. Thus, there are two possible
explanations: (1) DMA molecules became entrapped in the micelle core to form swollen micelles,
and/or (2) the Gelucire micelles grew or became
aggregated by the addition of DMA.
Polarity Inside Gelucire Micelles Coexisted
with Cosolvents
Figure 5 shows the polarity change inside
Gelucire micelles caused by the addition of the
cosolvents. As can be seen, the polarity increased
Figure 4. Scattered light intensity measurements
of the Gelucire solutions at 908. DMSO (open) or DMA
(closed) was added to the 15 w/v% (circle) or 7.5 w/v%
(triangles) aqueous Gelucire solutions.
SOLUBILIZATION BEHAVIOR OF POORLY SOLUBLE DRUGS
Figure 5. Fluorescent measurement of the 5 w/v%
Gelucire solutions with various cosolvent concentrations. I1/I3 is the intensity ratio of the first and the third
fluorescent peaks of pyrene (see text). The symbols are
the same as those for Figure 1. Error bars represent the
standard deviations.
with their addition for both cases, with the extent
of the increase being larger for DMA. However,
because the I1/I3 values for DMSO and DMA were
1.69 and 1.56 respectively, the polarity change
inside the micelles did not seem significant with
the addition of either cosolvent.
Solubilization of Phenytoin
As a poorly soluble model drug, phenytoin (PHT)
was employed first. Figure 6 shows the solubility
change of PHT on the addition of cosolvents. The
increase in the solubility followed the log-linear
Figure 6. Solubility of phenytoin in aqueous DMSO
(open) or DMA (closed) solution. The lines were drawn
from the best-fit of the log-linear model. Error bars
represent the standard deviations. For the DMA solutions, all error bars are hidden in the symbols.
1475
Figure 7. Solubility of phenytoin (squares) and indomethacin (circles) in aqueous Gelucire solution with
linear fit. Error bars represent the standard deviations.
model (eq. 1), and the solubilization capacity s
was determined as 6.7 for DMSO and 11.9 for
DMA. Figure 7 shows the solubility of PHT in the
aqueous Gelucire solution, which shows good
proportionality between Gelucire concentration
and solubility. The solubilizing capacity x was
determined as 8.1 mg/g. It should be noted that
pH value of the 20% Gelucire solution was 5.3,
which is well below pKa of PHT, 8.3.19 Therefore,
the change in pH due to the addition of the
Gelucire did not contribute to the bulk solubility
change, that is, p in eq. 3 was near unity.
Next the solubility of PHT in the Gelucire
solution, which contains various amounts of cosolvents, was evaluated. Figure 8 shows the
Figure 8. Solubility of phenytoin in the Gelucire/
DMSO/water solution with various DMSO concentrations. The Gelucire concentration was 15 w/v% (circle) or
5 w/v% (triangles). The thin lines are the expected values
from eq. 4. The thick lines are the best fits of the twophase model.
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KAWAKAMI, MIYOSHI, AND IDA
Figure 9. Solubility of phenytoin in the Gelucire/
DMA/water solution with various DMA concentrations. The Gelucire concentration was 15 w/v% (circle)
or 5 w/v% (triangle). The thin lines are the expected
values from eq. 4. The thick lines are the best fits of the
two-phase model.
observed PHT solubility in the Gelucire solution
combined with various fractions of DMSO. The
calculated solubility curves from eq. 4 and the twophase model (eq. 8) are also shown. The experimental solubility was much higher than Ss,
indicating some synergy effect between Gelucire
and DMSO. The two-phase model could successfully explain the experimental data using a as the
only fitting parameter. This trend was the same for
the DMA system as shown in Figure 9. The fitting
parameters obtained were shown in Table 1.
Figure 10. Solubility of indomethacin in aqueous
DMSO (open) or DMA (closed) solution. The lines were
drawn from the best-fit of the log-linear model. Error
bars represent the standard deviations.
by employing pKa ¼ 4.519 after the addition of
Gelucire. This contribution can apparently be
ignored in eq. 3, because the increase in the
solubility by the micelles was more than two
orders of magnitude. The linear relationship
between the solubility and the Gelucire concentration was observed as in the case of PHT, and
the solubility capacity x, 18.2 mg/g, was twice as
large as that for PHT. In this case, Ss could be
calculated by
Ss ¼ xðCs Ccmc Þ þ Scs ;
Solubilization of Indomethacin
Figure 10 shows the solubility of indomethacin
(IDM) in DMSO and DMA solutions. Unlike the
case of PHT, the addition of a small amount of
cosolvent decreased the solubility. Thus, the loglinear model did not work for these cases. The
solubility of IDM in the aqueous Gelucire solution
is shown in Figure 7. The pH of the saturated
aqueous solution of IDM was 5.6, giving p ¼ 0.54
ð10Þ
where Scs is the solubility of IDM in the aqueous
cosolvent solution. Figures 11 and 12 show the
measured solubility of IDM in the Gelucire–
DMSO and Gelucire–DMA solutions, presented
together with the calculated solubility curves. As
for the cases of PHT, the solubility values of IDM
could not be explained by eq. 10 but reproduced by
the two-phase model using s as a fitting parameter. The fitting parameters for IDM were also
presented in Table 1.
Table 1. Fitting Results of the Solubility Data
5% Gelucire
a
s
x/Sw
15% Gelucire
PHT-DMA
IDM-DMA
PHT-DMSO
IDM-DMSO
PHT-DMA
IDM-DMA
PHT-DMSO
IDM-DMSO
0.99
11.9
293
0.99
12.5
1049
0.97
6.7
293
0.97
8.0
1049
0.93
11.9
293
0.93
9.4
1049
0.68
6.7
293
0.68
6.6
1049
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 93, NO. 6, JUNE 2004
SOLUBILIZATION BEHAVIOR OF POORLY SOLUBLE DRUGS
Figure 11. Solubility of indomethacin in the Gelucire/DMSO/water solution with various DMSO concentrations. The Gelucire concentration was 15 w/v%
(circle) or 5 w/v% (triangles). The thin lines are the
expected values from eq. 4. The thick lines are the best
fits of the two-phase model.
DISCUSSION
Micelle Morphology Change by
Cosolvent Addition
The surface tension and the fluorescent measurements suggested the micelle formation of Gelucire
both in water and the 10% cosolvent solutions.
Although the addition of cosolvents increased the
monomer concentration, this effect was negligible
for the solubilization behavior of the guest molecules, because the Gelucire concentrations studied
were more than three orders of magnitude higher
than the critical micellar concentrations. The
1477
more important contribution of the cosolvents
seemed to be a change in the micellar characteristics. According to the model calculation, the
cosolvents incorporated in the micelle phase were
below 10% in most cases. Interestingly, the lightscattering study proved that DMSO and DMA
affected the micelle morphology in different ways.
DMSO might act as an anchor to the interfacial
layer of the micelles to decrease the micelle size,
because the light-scattering intensity did not increase at all, despite the increased volume fraction of the micelles. On the other hand, DMA
seemed to penetrate deeper into the micelle to
form the DMA core. However, this was not enough
to explain the dramatic increase in the lightscattering intensity, because the incorporated
fraction of DMA molecules seemed to be very
small according to the model calculation. If we
suppose that 10% of the added DMA is entrapped
in the Gelucire micelle core, the volume fraction of
the micelles becomes approximately 17% after the
addition of 20% DMA. This means only a 4%
increase in the diameter. If the DMA molecules
are also distributed to the interfacial layer, this
increase becomes much smaller. The fluorescent
measurements did not support the DMA pool
formation either, because the I1/I3 value did not
increase enough. (It should be noted that pyrene
molecules might be located not in the DMA pool,
although it was formed, but in the micelle
interfacial layer.) These observations imply that
the micelle growth and/or the formation of the
aggregates might also occur. The different effects
of DMSO and DMA were likely to have been
caused by the difference in the depth of the penetration in the interfacial layer of the micelles.
Applicability of the Solubility Model
Figure 12. Solubility of indomethacin in the Gelucire/DMA/water solution with various DMA concentrations. The Gelucire concentration was 15 w/v%
(circle) or 5 w/v% (triangles). The thin lines are the
expected values from eq. 4. The thick lines are the best
fits of the two-phase model.
We proposed a simple solubility model for combined use of the surfactant and the cosolvents. In
the study of PHT, rather good agreement was
obtained between the theoretical and experimental results, although a was the only fitting parameter in the calculation. The obtained a values,
0.97 for DMSO and 0.99 for DMA, were quite
reasonable because of their miscible characteristics with water. Therefore, the two-phase model
seemed to work well, if the log-linear model is
applicable to the solubility of the drug in the
cosolvent–water mixture.
The log-linear model could not explain the
IDM solubility in the cosolvent–water mixture. Although this phenomenon was not studied
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 93, NO. 6, JUNE 2004
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KAWAKAMI, MIYOSHI, AND IDA
further, this might be caused by a preferred interaction between cosolvent and water molecules.
DMSO has been known to form 1:2 complex with
water molecules when the DMSO concentration is
below 10%,20,21 and DMA may act in a similar way.
This interaction may decrease the IDM solubility.
In the fitting procedure, we employed a values
obtained from the PHT study. Thus, the only
fitting parameter was s, which could not be calculated in the solubility measurements. In this case,
s includes the deviation of the solubility from the
log-linear model as well as the solubilization
capacity of the cosolvent. It should also be mentioned that we obtained almost the same a and
s values, if a was also considered as a fitting
parameter.
The two-phase model was confirmed to be a good
approximation regardless of the solubility profile
of the drugs to the water–cosolvent mixture. If
the solubility profile follows the log-linear model,
like PHT, the partition of the cosolvent between
the micelle phase and the continuum phases, a, is
the only fitting parameter to explain the solubility in the surfactant–cosolvent–water mixture.
Although the determination of s and x in the
preliminary experiments is recommended, similar
results could be obtained by the best-fit analysis
without knowing those values. Even though the
solubility profile does not obey the log-linear
model, like IDM, the same analysis was possible.
In this study, only Gelucire 44/14 was employed as
surfactant. We are planning to extend this analysis to other surfactants, cosolvents, and drugs.
Practical Implications for Using
Gelucire/Cosolvent Mixtures in Screening Studies
The combined use of Gelucire and cosolvents is
not a new idea in the pharmaceutical industry for
solubilizing poorly soluble drugs, although little
has been discussed in literature. The use of cosolvent facilitates the preparation procedure of
the solution, because, in many cases, new candidate drugs are supplied as DMSO solution in the
screening process. Our important finding here is
that the addition of cosolvents did not contribute
much to improving the solubility. For example,
in the IDM–DMSO system, the increase in
the solubility by the addition of 15% DMSO to
a 15% Gelucire solution was only 1.2 times. The
solubilization capacity of cosolvents for poorly
soluble drugs is frequently much lower than that
of micelles. In those cases, the effect of cosolvents
on the micellar characteristics is much more
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 93, NO. 6, JUNE 2004
important than their direct contribution to the
drug solubility.
CONCLUSIONS
The solubility of poorly soluble drugs in Gelucire
solution containing DMA or DMSO was investigated, and a two-phase model was introduced
to explain the solubility data. Gelucire was confirmed to form micelles both in water and water/
cosolvent mixtures. Light-scattering measurements revealed that DMA induce large micellar
aggregates by being entrapped in the micelles
and/or inducing aggregation. However, DMSO
was likely to be anchored to the interfacial layer
and did not induce micelle growth. Two poorly
soluble drugs, phenytoin and indomethacin, were
employed as the model drugs. Their solubility in
the mixtures could be well explained by using our
two-phase model, which requires only one fitting
parameter. Addition of the cosolvents to the
Gelucire solution had only a little advantage from
the viewpoint of improving solubility.
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