International Journal of Pharmaceutics 271 (2004) 11–19

Characterization of caprylocaproyl macrogolglycerides based

microemulsion drug delivery vehicles for an amphiphilic drug
Ljiljana Djordjevic∗ , Marija Primorac, Mirjana Stupar, Danina Krajisnik
Department of Pharmaceutical Technology and Cosmetology, Faculty of Pharmacy,
Vojvode Stepe 450, P.O. Box 146, 11221 Belgrade, Serbia and Montenegro
Received 5 March 2003; received in revised form 29 September 2003; accepted 21 October 2003

Abstract
Microemulsion systems composed of water, isopropyl myristate, PEG-8 caprylic/capric glycerides (Labrasol® ), and
polyglyceryl-6 dioleate (Plurol Oleique® ), were investigated as potential drug delivery vehicles for an amphiphilic model drug
(diclofenac diethylamine). Pseudo-ternary phase diagram of the investigated system, at constant surfactant/cosurfactant mass
ratio (Km 4:1) was constructed at room temperature by titration, and the oil-to-surfactant/cosurfactant mass ratios (O/SC) that
exhibit the maximum in the solubilization of water were found. This allowed the investigation of the continuous structural
inversion from water-in-oil to oil-in-water microemulsions on dilution with water phase. Furthermore, electrical conductiv-
ity (σ) of the system at Km 1:4, and O/SC 0.250 was studied, and the percolation phenomenon was observed. Conductivity
and apparent viscosity (η ) measurement results well described colloidal microstructure of the selected formulations, including
gradual changes during their formation. Moreover, σ, η , and pH values of six selected microemulsion vehicles which differ in
water phase volume fraction (Φw ) at the selected Km and O/SC values, were measured. In order to investigate the influence of
the amphiphilic drug on the vehicle microstructures, each system was formulated with 1.16% (w/w) diclofenac diethylamine.
Electrical conductivity, and η of the investigated systems were strongly affected by drug incorporation. The obtained results
suggest that diclofenac diethylamine interacts with the specific microstructure of the investigated vehicles, and that the different
drug release kinetics from these microemulsions may be expected. The investigated microemulsions should be very interesting
as new drug carrier systems for dermal application of diclofenac diethylamine.
© 2003 Elsevier B.V. All rights reserved.
Keywords: Microemulsion; Caprylocaproyl macrogolglycerides; Percolation; Drug delivery; Diclofenac diethylamine

1. Introduction In spite of numerous advantages in comparison with

other colloidal vehicles, microemulsions often require
Microemulsion systems, owing to their pharma- a high content of surfactant that can lead to skin irri-
ceutical advantages (thermodynamic stability, ease of tation (Kumar and Mital, 1999; Lawrence and Rees,
preparation, transparency, low viscosity, considerable 2000). The concentration of surfactant can sometimes
potential for solubilizing variety of drugs) are the be reduced by the addition of cosurfactants (Sagitani
object of investigations in relation to drug delivery. and Friberg, 1980). The majority of the work reported
in the scientific literature concerns microemulsion
∗ Corresponding author. Tel.: +381-11-397-0379; systems based on pharmaceutically unacceptable
fax: +381-11-397-2408. cosurfactants such as short- or medium-chain alco-
E-mail address: [email protected] (L. Djordjevic). hols (Kumar and Mital, 1999; Lawrence and Rees,

0378-5173/$ – see front matter © 2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.ijpharm.2003.10.037
12 L. Djordjevic et al. / International Journal of Pharmaceutics 271 (2004) 11–19

2000). The good biological acceptance of non-ionic diethylamine is a nonsteroidal anti-inflammatory

surfactants (Kibbe, 2000) as well as ability to form drug able to form micelles and lyotropic liquid
microemulsions that are insensitive to pH and elec- crystals in water (Kriwet and Müeller-Goymann,
trolyte concentration are the main motives for their 1993). The interactions of diclofenac diethylamine
extensive use (Kumar and Mital, 1999; Lawrence with phospholipids have been reported (Engehausen
and Rees, 2000). It has been recently reported that and Müeller-Goymann, 1992). Such interactions be-
certain mixtures of non-ionic surfactants can provide tween drug molecule and components of pharma-
enhancement of solubilization of water in water-in-oil ceutical formulations may strongly influence drug
microemulsions (Hiuberts and Shah, 1997; Sagitani release (Müeller-Goymann et al., 1995; Kriwet and
and Friberg, 1980). There have been several stud- Müeller-Goymann, 1993).
ies involving low-irritant caprylocaproyl macro- There were three specific objectives in the present
golglycerides based microemulsions as drug de- study. First, we wanted to formulate different types
livery vehicles for topical application (Gašperlin of microemulsion vehicles stabilized with a mini-
and Špiclin, 2001; Delgado-Charro et al., 1995; mum amount of caprylocaproyl macrogolglycerides/
Kreilgaard, 2001). In order to facilitate caprylocaproyl polyglyceril-6 dioleate mixture in order to obtain
macrogolglycerides based microemulsions formation, low-irritant microemulsion vehicles for cutaneous
the surfactants based on polyglycerol fatty acid es- application. Second, we wanted to investigate the
ters have been used as cosurfactants (Gašperlin and gradual changes in the microstructure with the ad-
Špiclin, 2001; Delgado-Charro et al., 1995; dition of water phase into the mixture of oil and
Kreilgaard, 2001). All the same, it has been recently surfactants during the preparation of the microemul-
reported that caprylocaproyl macrogolglycerides bas- sions. Third, we have investigated the influence of
ed microemulsion systems incorporating isopropyl diclofenac diethylamine on the stability, optical tex-
myristate as oil phase, have a large microemulsion ture, conductivity, and rheological properties of the
region in their phase diagrams (Choi et al., 1997). selected microemulsion formulations.
Due to the variety of structures occurring in them
(water-in-oil (W/O), oil-in-water (O/W), or bicon-
tinuous structures in which water continuous and 2. Materials and methods
oil continuous domains are separated by surfactant
monolayers), microemulsions display a rich behavior 2.1. Materials
regarding the release of solubilized material. Also,
one can reach sustained release if the interactions PEG-8 caprylic/capric glycerides (Labrasol® ) and
between drug and surfactant and/or partitioning of polyglyceryl-6 dioleate (Plurol Oleique® ) were a kind
the drug between oil and water phases strongly affect gift from Gattefosse (Lyon, France). Isopropyl myris-
the drug release (Kumar and Mital, 1999). In order tate was supplied by Cognis GmbH (Düsseldorf, Ger-
to investigate a drug delivery potential of microemul- many). Water was purified by double distillation in
sion vehicles, it is necessary to characterize their a glass apparatus and then deionized using Millipore
microstructure as well as a microstructure of drug Milli-Q® Water System (Millipore Corporation, Bed-
loaded microemulsions. The formation process and ford, USA). Diclofenac diethylamine was a kind gift
gradual changes in microemulsion microstructure can of Hemofarm a.d. (Vrsac, Yugoslavia). All substances
be monitored quantitatively by measuring the electri- were used as received without further purification.
cal conductivity and rheological properties of system
(Kumar and Mital, 1999; Lawrence and Rees, 2000). 2.2. Microemulsion preparation
Apart from the microemulsion structure and compo-
sition, the incorporated drug molecules participate in 2.2.1. Construction of phase diagram
the microstructure of the system and may influenced The pseudo-ternary phase diagram was constructed
it due to molecular interactions, especially if the by titration of homogenous liquid mixtures of oil,
drug possesses amphiphilic and/or mesogenic prop- surfactant, and cosurfactant, with water at room tem-
erties (Müeller-Goymann et al., 1995). Diclofenac perature (Gattefossé, 1994). Labrasol® , the surfactant
 L. Djordjevic et al. / International Journal of Pharmaceutics 271 (2004) 11–19 13

Fig. 1. Pseudo-ternary phase diagram with the microemulsion existance region (the shaded area) of water (W)/PEG-8 caprylic/capric
glycerides (S)/polyglyceryl-6 dioleate (C)/isopropyl myristate (O) system at Km 4:1. Diagram was studied at room temperature. The
selected O/SC 0.250 represents the continuous changes in the investigated systems compositions (A–F) during their formation.

(S), and Plurol Oleique® , the cosurfactant (C), were Labrasol® /Plurol Oleique® mixture with O/SC 0.250
weighed in the same screw-cap dark-brown glass was selected (Fig. 1). Furthermore, six potential mi-
vial, vortexed vigorously for 1 h, and then stored croemulsion vehicles (refereed to as A–F in Table 1
overnight at room temperature. At Km 4:1 mixtures and Fig. 1) different from each other by Φw , were se-
of oil phase (O), and surfactant/cosurfactant blend lected and prepared at Km 4:1 and O/SC 0.250. For the
were prepared, where contents of oil and amphiphile preparation of the microemulsion vehicles appropriate
blend in the mixtures were varied from 9:1 to 1:9. quantities of Labrasol® , Plurol Oleique® , isopropyl
Water phase was added drop by drop, under magnetic myristate, and water were weighed into the screw-cap
stirring, to each oily mixture. During the titration, glass vial. The mixtures were stirred with a magnetic
samples were stirred to allow equilibration. Following bar to speed up the formation of the transparent sys-
the addition of aliquot of water the mixture was vi- tems, at room temperature. Transparent, single-phase
sually examined for transparency. The changes in the formulations were formed in a few seconds. Further-
sample visual aspect from turbid to transparent and more, in order to evaluate their drug delivery poten-
inversely were observed. Transparent, single-phase, tial for an amphiphilic model substance, diclofenac
low viscous mixtures were designated as microemul- diethylamine was dissolved into preweight vehicles at
sions. After the water titration, in order to establish
the microemulsion region borders, titration of water
and surfactant/cosurfactant mixtures with oil were Table 1
performed, in the same manner. Microemulsion vehicle compositions (% (w/w))
A B C D E F
2.2.2. Selection of microemulsion formulations for Water 10.0 20.0 30.0 40.0 50.0 60.0
detailed studies Isopropyl myristate 18.0 16.0 14.0 12.0 10.0 8.0
For further studies, from the constructed pseudo- Labrasol® /Plurol 72.0 64.0 56.0 48.0 40.0 32.0
ternary phase diagram, one initial isopropyl myristate/ Oleique®
14 L. Djordjevic et al. / International Journal of Pharmaceutics 271 (2004) 11–19

a concentration ratio of 1.16% (w/w). Both, unloaded 2.3.5. pH

and drug-loaded microemulsions were prepared 48 h The pH values of the samples were measured by
before investigations (we can reasonably assume that a pH meter (model HI 8417, Hanna Instruments Inc.,
the drug distribution among the oil, water and surfac- Woonsocket, USA), at 20 ± 1 ◦ C.
tant micelles, attains the termodynamic equilibrium)
and stored at room temperature. 2.3.6. Partition coefficient
The drug partition coefficient (Kp ) at 20 ± 1 ◦ C
2.3. Microemulsion characterization was calculated according to the concentration of drug
remained in water phase of water/isopropyl myris-
2.3.1. Polarized light microscopy tate system after 72 h. Diclofenac diethylamine con-
Both, unloaded and drug-loaded vehicles were ex- centration was determined spectrophotometrically at
amined by polarized light microscopy (Aus Jena polar- 275.1 nm (Spectrophotometer Carry 50, Varian, Ger-
izing microscope, Carl Zeiss, Oberkochen, Germany) many).
in order to determine optical isotropy of the samples.
The observing whether the sample rotates the plane
of polarization of polarized light is very useful tool to 3. Results and discussion
distinguish isotropic microemulsions from anisotropic
lamellar and hexagonal mesophases. 3.1. Phase behavior

2.3.2. Centrifugation Pseudo-ternary phase diagram of the investigated

In order to eliminate metastable systems, the se- quaternery system water/caprylocaproyl macrogolgly-
lected microemulsion vehicles as well as drug-loaded cerides/polyglyceryl-6 dioleate/isopropyl myristate
microemulsions were centrifugated (Sigma 2–16 cen- is presented in Fig. 1. Formation of microemulsion
trifuge, Sigma Laborzentrifugen GmbH, Osterode, systems (the shaded area) was observed at room tem-
Germany) at 13,000 min−1 for 30 min. perature. Phase behavior investigations of this system
demonstrated the suitable approach to determine the
2.3.3. Conductivity measurements water phase, oil phase, surfactant, and cosurfactant
The solubilization of water phase in the selected concentrations for which the transparent, one-phase,
oily mixture was monitored quantitatively by measur- low-viscous systems form. During the addition of
ing the electrical conductivity. The water phase was water in the selected oily mixtures there was con-
added drop by drop in the initial mixture of oil and tinuous transition from oil-rich systems (right side
amphiphiles, and measured σ of formulated samples, of phase diagram) to water-rich systems (left side of
using a conductometer CDM 230 (Radiometer, Copen- phase diagram). The obtained results show that the
hagen, Denmark), at 20 ± 2 ◦ C and the frequency of maximum solubilization of water was achieved in
94 Hz. Additionally, the conductivity of microemul- the oil/surfactant/cosurfactant mixtures with O/SC <
sion vehicles and drug-loaded microemulsions was 0.250. The maximum percentages of water phase
measured. were 75.83% (w/w) for O/SC 0.250 (the content of
surfactant/cosurfactant mixture was 19.34% (w/w)
2.3.4. Rheological measurements and 89.64% (w/w) for O/SC 0.111 (the concentration
Rheological behavior of the unloaded and drug- of amphiphiles mixture was 9.32% (w/w)). With the
loaded microemulsions was evaluated using a reduction of an amphiphiles content (O/SC > 0.250)
rotational rheometer coupled with cup and bob mea- the oil/surfactant/cosurfactant mixtures were less able
suring device (Rheolab MC120, model Z3 DIN, to solubilize the water phase. Additionally, we have
Paar Physica, Stuttgart, Germany). Apparent viscos- been investigated the structural changes in the se-
ity data at shear rate (γ) 200 s−1 , were obtained at lected system with increasing Φw at constant O/SC
20 ± 1 ◦ C. Experiments were carried out in tripli- 0.250, in order to ascertain whether any relationship
cate for each sample, and results were presented as exists between both the electroconductive behavior
average ± S.D. and viscosity, and microstructure. Furthermore, from
 L. Djordjevic et al. / International Journal of Pharmaceutics 271 (2004) 11–19 15

120

100

80
σ (µ S/cm)

60

40

20

0
0 20 40 60 80
Φw (% w/w)

Fig. 2. Electrical conductivity (σ) as a function of water phase volume fraction (Φw ) in the system with O/SC 0.250 and Km 4:1.

the above-mentioned investigations, six potential mi- Lagues, 1979; Strey, 1996). While the water volume
croemulsion vehicles (A–F) were selected. The Km fraction increases, the electrical conductivity of these
and O/SC values were constant, but the percentages of systems slightly increases as well until the critical Φw
surfactant/cosurfactant mixture as well as water and is reached when a sudden increase in conductivity is
oil phases of the vehicles were different, and it was observed. This phenomenon is known as percolation,
reasonably to expect the different types of colloidal and the critical Φw at which it is occurs is known
microstructure. as percolation threshold (Φp ) (Bennett et al., 1982).
The investigated microemulsion system, containing
3.2. Conductivity measurements and apparent non-ionic amphiphiles, exhibited electroconductive
viscosity behavior in spite of its non-ionic type. In the region of
low water contents a W/O microemulsion is formed.
The electrical conductivity of the selected oily mix- Beyond the percolation threshold (Φp ≈ 10% (w/w))
ture, as a function of Φw , is presented in Fig. 2. Ac- conductivity increases linearly and sharply up to Φw ≈
cording to obtained conductivity data, the investigated 50% (w/w). It can be concluded that beyond Φp a net-
microemulsions can be designed as a type of systems work of conductive channels exists, which corresponds
where the σ is fairly high and varies with Φw . The to the formation of water cylinders or channels in an
electrical conductivity of the selected oily mixture was oil phase due to the attractive interactions between the
almost zero as long as the Φw was smaller than 10% spherical microdroplets of water phase in the W/O mi-
(w/w). During the water titration up to Φw ≈ 50% croemulsion. For the Φw > 50% (w/w) the electrical
(w/w), σ increases fast. At Φw > 50% (w/w), the con- conductivity increases non-linearly up to a maximum
ductivity of the system was no significantly affected at Φw ≈ 60% (w/w). After the maximum, conductiv-
by the further addition of water. It has been previ- ity of the system was slightly decreased by the further
ously demonstrated that there is a strong correlation addition of water phase, and these conductivity data
between specific structures of microemulsion systems can be explained by the dilution of O/W microemul-
composed of ionic surfactants, and their electrocon- sion with the added water which decreased the concen-
ductive behavior (Bennett et al., 1982; Borkovec tration of the dispersed oil droplets. Thus, the σ–Φw
et al., 1988; Clausse et al., 1987; Kahlweit et al., 1987; curve illustrates the occurrence of the three struc-
16 L. Djordjevic et al. / International Journal of Pharmaceutics 271 (2004) 11–19

Table 2
Electrical conductivity (σ), apparent viscosity (η ), and pH of the unloaded vehicles A–F, and the vehicles loaded with diclofenac
diethylamine (1.16% (w/w)) studied
Formulation Unloaded vehicles Drug-loaded vehicles

σ (␮S/cm) η (mPa s) pH σ (␮S/cm) η (mPa s) pH

O/SCa – 86.2 ± 0.0003 – – 88.7 ± 0.0001 –

A 2.9 120.0 ± 0.0005 7.13 3.8 128.0 ± 0.0007 7.41
B 10.3 111.0 ± 0.0021 7.33 23.5 112.0 ± 0.0015 7.45
C 27.2 91.6 ± 0.0005 7.62 62.1 92.0 ± 0.0005 7.70
D 52.5 78.1 ± 0.0002 7.59 122.3 92.0 ± 0.0005 7.65
E 80.5 77.9 ± 0.0001 7.49 208.5 96.0 ± 0.0001 7.55
F 94.3 34.7 ± 0.0005 7.25 285.7 55.0 ± 0.0002 7.38
a OSC, mixture of isopropyl myristate, Labrasol® , and Plurol Oleique® .

tural regions: W/O (Φw < 10% (w/w)), nonspherical from 0 to 10% (w/w). It is well known that increasing
W/O–bicontinuous–non-spherical O/W (10% (w/w) of volume fraction of dispersed phase in microemul-
< Φw < 50% (w/w)), and O/W (Φw > 50% (w/w)). sions brings to increase of viscosity (Bennett et al.,
Correlation between the results of the examination 1982), and it could be expected that viscosity changes
of the phase behavior and the results of conductivity reflects a transformation of system microstructure in
measurements was a good foundation for further anal- the function of Φw . Initial increase of viscosity with
yses of the system structure by applying rheological increase of Φw is probably the consequence of attrac-
measurements. The dependence of the apparent vis- tive interaction and aggregation of droplets of water
cosity of the investigated formulations on the water phase including molecular reorganization on the in-
phase concentration is shown in Table 2 and Fig. 3. terface. Position of the maximum η –Φw curve is at
All tested samples were liquids of low viscosity (η water phase of about 10% (w/w). Similar increase of
101 –102 mPa s). Obtained η –Φw curve shows that η viscosity with the change of quantitative relations in
increases from 86.2 to 120 mPa s with increasing Φw the system which leads to forming of the bicontinu-

0.14

0.12

0.1

0.08 M
DDA

0.06

0.04

0.02

0
0 10 20 30 40 50 60 70

Fig. 3. Apparent viscosity (η ) of unloaded (M) and drug loaded (DDA) microemulsions as a function of water volume fraction (Φw ) in
the system with O/SC 0.250 and Km 4:1.
 L. Djordjevic et al. / International Journal of Pharmaceutics 271 (2004) 11–19 17

ous structure from droplet-like formation is detected at clofenac diethylamine strongly affected electrical con-
different microemulsion systems which are, till now, ductivity of microemulsion vehicles (Table 2, Fig. 4).
investigated. However, bicontinuous structure of liq- Conductivity values for drug loaded microemulsions
uid microemulsions is more like to be linked to lower were increased by about a factor 2–3 in comparison to
value of viscosity (Kahlweit et al., 1987). Measured microemulsions without a drug (Fig. 4). The influence
values of η of this samples decrease from 120 to of the active ingredient on the η of the microemulsion
34.7 mPa s with increase of water phase concentration formulations is presented in Table 2 and Fig. 3. The η
from 20 to 60% (w/w). On η –Φw curve it can be of the drug loaded microemulsions were higher than
noted that η decreased very slowly at 20% (w/w)< the unloaded vehicles apparent viscosities. Also, the
Φw < 50% (w/w), which probably suggests transfor- addition of diclofenac diethylamine changed the bi-
mation of system structure from oil continuous (when continuous regime of the microemulsions microstruc-
the water phase content in the system is less than 20% ture (Fig. 3). The possibility of measuring the drug par-
(w/w)), via bicontinuous, to water continuous (when tition between the oil and the water phases in the pres-
the water phase content in the system is greater than ence of the surfactant at the oil–water interface is still
50% (w/w)). The obtained η –Φw curve can be well an impossible task with common techniques. Thus,
described by a polynomial equation. Polynomial de- the extremely low drug partition coefficient between
pendency of viscosity of the system on content of dis- isopropyl myristate and water phases at 20 ± 1 ◦ C (kp
persed phase in the system shows the presence of non- 0.0708) is useful only to emphasize the very low drug
spheric aggregates of dispersed phase. solubility in oil the oil phase. We can assume that
The percolation phenomenon observed in investi- at higher water content and lower surfactant and oil
gated systems as well as rheological measurements concentrations in the system, diclofenac diethylamine
results were convincing evidence that system un- is predominantly partitioned between the water phase
dergoes a structural inversion from oil-continuous and a surfactant/cosurfactant interfacial film, con-
to water-continuous over bicontinuous structure as tributing the elevated electrical conductivity as well
a function of increasing Φw , at fixed temperature. as higher viscosity of bicontinuous microemulsion
Moreover, the electrical conductivity data and viscos- system. The low pKa value (pKa 4.87) (Ledvige and
ity measurements allow us to quantitatively identify Corrigan, 1998), and latter experimental results sug-
bicontinuous structure from droplet microemulsion gest that the presence of diclofenac diethylamine in the
structures. The molecular origin of this statement is investigated microemulsion systems increases σ due
likely the transformation of the interfacial film curva- to passage of dethylamonnium cations through chan-
ture by the lowering of surfactant/cosurfactant content nels formed by collision of droplets of water phase.
as well as changing the contents of the water and oil It is known that water solutions of diclofenac diethy-
phases. Also, based on the conductivity and viscosity lamine at room temperature at concentrations above
results, the microemulsion system A is W/O type, 0.74% form vesicles (critical association concentra-
B, C, and D, are W/O type with nonspherical iso- tion at 20 ◦ C is 20 mM; Kriwet and Müeller-Goymann,
lated droplet structure (possibly locally cylindrical) 1993). Taking the results of examining of partition
or bicontinuous, and E and F are O/W type. coefficient it can be supposed that in examined mi-
Furthermore, there have been tested optical texture croemulsions with large concentration of water phase
and stability, and measured pH of the selected for- came to forming of aggregates of the drug molecules,
mulations. Physico-chemical characterizations were which reflects on the apparent viscosity of the sys-
performed on both unloaded and drug-loaded mi- tem. In the formulations which are proved to have
croemulsions. The systems were isotropic, transparent cylindrical and bicontinual structure, diclofenac di-
dispersions and after centrifugation no phase separa- ethylamine is probably located in the interfacial film
tion could be observed. Microemulsion vehicles pH of tensides and it could not affect the viscosity of the
values were in a range of 7.13–7.62 (Table 2). The system. In the samples with low water content and
incorporated drug did not affect the optical texture of high amphiphiles concentrations, diclofenac diethy-
the microemulsion formulations and did not influence lamine is most likely solubilized in the oil-continuous
significantly pH values of the vehicles (Table 2). Di- system.
18 L. Djordjevic et al. / International Journal of Pharmaceutics 271 (2004) 11–19

300

250

200
M DDA
σ (µS/cm)

150

100

50

0
0 10 20 30 40 50 60 70
Φw (% w/w)

Fig. 4. Electrical conductivity (σ) of unloaded (M) and drug loaded (DDA) microemulsions.

We demonstrate the relatively simple experimen- References

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