Journal of Control~~ Release, 10 (1989) 237-243 237

Elsevier Science Publishers B.V., Amsterdam - Printed in The ~etherl~~

RELEASE OF DRUGS FROM OIL-WATER MICROEMULSIONS

M. Trotta, M.R. Gasco* and S. Morel

Dip&memo di Scienza e Tecnologia de/ Farmeco, c.so Raffaello 3 1, Turin (Italy)

(ReceivedJanuary 27, 1987; accepted in revised form April 4, 1989)

Key words: oil-water microemuisjons;drug release; partition coefficients; hydrophilicmembranes

The release of five drugs with different lipophilicities from oil-water (o/w) microemulsions (iso-
propyl myristate as oil, 1-butanol as cosurfactant, aerosol-OT as surfactant and buffer, pH 7.0, as
the aqueous phase) was studied by determining mass transfer constants of the drugs through a
hydrophilic membrane separating the o/w microemulsions from the receiving aqueous phase. Tk
initial mass transfer constants measured were linearly related to the partition coefficients (P,,J
of the drugs in the oil-cosurfactant-water mixtures. The P,, values were used to approximate
the drug concentration in the aqueous phase of the emulsion. The initial mass transfer constants
of different drugs calculated on the basis of these co~entrat~~ were very similar to the mass
tra~fer Montana of the drugs obtai~d ~~r~at~n studies thro~h the same auras using
an ~~o~p~e.

INTRODUCTION absence of drug [4]. In the present paper, the

The release rates of drugs from microemul-
sions are of interest both for the application of
microemulsions in the pharmaceutical field and
for the evaluation of the physical properties of
the system. The use of microemulsions as pos-
sible therapeutic systems has been predicted by
several authors [ 1-3 1. Because of the high sta-
bility of the microemulsions, it is not possible
to determine the concentration of the drug in
both phases directly. The presence of a cosur-
factant, usually an alcohol, further complicates
the situation, because this compound parti-
tions between the phases.
In a previous study, the physicochemical
properties of oil-water (o/w) and w/o microe-
mulsions containing butanol, aerosol-OT, water
and isopropyl myristate were examined in the
*To whom correspondence should be addressed.
release of five drugs with different lipophilici-
ties from the o/w microemulsion, as described
above [4], was studied. The release of a com-
pound from a microemulsion depends on var-
ious process parameters, such as the oil-aqueous
phase ratio, the droplet size, the distribution of
the drug in the phases of the micr~mulsion
system and the rate of vision in both phases
[5-71.
It may be anticipated that the initial permea-
tion rate of a compound through a hydrophilic
membrane contacting the microemulsion will
depend on the concentration of the compound
in the aqueous phase of the microemulsion. The
aim of this study was to determine the initial
permeation rates of drugs with different lipo-
philicities incorporated in oil-water microe-
mulsions through a hy~ophilic membrane, and
to examine whether these permeation rates can
be related to the partition coefficients of the

0168-3659/89/$03.50 0 1989 Elsevier Science Publishers B.V.

drugs in oil-buffer-1-butanol mixtures simu-
lating the emulsion.
MATERIALS AND METHODS
Nitrofurazone, phenylbutazone, prednisone,
betamethasone and, menadione were used, as
obtained from Aldrich Chemical Co. (Milwau-
kee, WI, U.S.A.). Microemulsions were pre-
pared using sodium bis (2-ethylhexyl) sulpho-
succinate ( AOT) , isopropyl myristate (IPM )
and 1-butanol from Merck (Darmstadt,
F.R.G. ). Other chemicals were of analytical
grade. The membranes SM 15714 (cellophane)
and SM 15712 (cellulose nitrate) were ob-
tained from Sartorius (Giittingen, F.R.G. ). The
membrane Servapor 44155 (cellulose) was from
Serva (Heidelberg, F.R.G. ) .
Instruments: UV-visible spectrophotometer
Varian DMSS 80 (Springvale, Australia), pH
meter Orion 701A (Cambridge, MA, U.S.A.),
He-Ne ion laser and K7025 multibit correlator
from Malvern (Malvern, Worcs., Great
Britain).
Diffusion apparatus
Determinations of drug release rates from
aqueous solution and from microemulsions were
carried out in an apparatus consisting of a do-
nor and a receptor compartment, each with a
volume of 20 ml. The receptor compartment was
connected, via a peristaltic pump, to a larger
stirred reservoir acting as a sink (200 ml). The
contents of each compartment were stirred by
a matched set of bar magnets. The magnetism
were rotated by a pair of synchronous motors,
located directly underneath the cell. The rota-
tion speed was 300 rpm. The effective surface
area of the membrane was 3.14 cm’, and the
whole apparatus was submerged in a waterbath
thermostated at 37 oC.
Preparation of microemulsions
(a) With a fixed amount of butanol
The o/w microemulsions were prepared us-
ing AOT as emulsifier, IPM as oil phase and l-
butanol as coemulsifier. Phosphate buffer (13
ml, 0.025 A4, pH 7.0) was added to a 50 ml test
tube containing 4.5 ml of IPM, 2.5 ml of l-bu-
tanol and 2.0 g of AOT.
Nitrofurazone, phenylbutazone or predni-
sone was dissolved in buffer, and betametha-
sone or menadione in the oil phase. The test
tube was stoppered tightly and shaken, giving a
stable o/w microemulsion. Each microemul-
sion batch was prepared in triplicate. The mean
droplet size, determined using photon correla-
tion spectroscopy (PCS) [8,9], was 34 nm, both
in the presence and in the absence of the drugs.
(b) With different amounts of butanol
A series of microemulsions containing differ-
ent amounts of butanol was used for studying
prednisone release. The amounts of emulsifier,
oil and buffer were the same as mentioned
above, and the amount of coemulsifier was 2.0,
2.5,3.0 or 3.5 ml, respectively.
Permeability experiments
The permeability experiments were per-
formed with (a) drugs in aqueous solution, (b)
drugs dissolved in microemulsions, and (c)
prednisone dissolved in microemulsions with
different concentrations of butanol.
In method (a), 18.8 ml of 0.025 M phosphate
buffer solution, pH 7.0, containing a fixed con-
centration of each drug (5.0 x 10m4M) and 6.0%
(v/v) of butanol was used.
In method (b) 20.0 ml of a standard microe-
mulsion containing a 4.0 X 10m4-3.0 X low3 M
concentration of each drug was employed as do-
nor phase.
In method (c), 20.0 ml of a particular mi-
croemulsion containing 5.0 X 10d4 M predni-
sone was used as donor phase. All diffusion ex-
periments were performed using a receptor
solution of 0.025 A4phosphate buffer (pH 7.0)
containing 6.0% (v/v) of butanol.
Two different types of membrane were used:
a dialysis membrane (Servapor 44155) and an
artificial double-layer membrane composed of
two layers, viz. a barrier foil, type SM 15714
(soaked in water until swollen), and a mem-
brane filter, type SM 15712, impregnated with
dodecanol as lipid barrier. The two layers were
pressed together to form a hydrophilic/lipo-
philic double layer; the SM 15714 membrane
was selected in order to prevent damage of the
lipid membrane. The appearance of the drug in
the receptor compartment was monitored by a
flow cell UV spectrophotometer (nitrofura-
zone, log e370=4.16; phenylbutazone, log
~~~~~4.24; prednisone, log ezaO= 4.16; betame-
thasone, log t240=4.11; menadione, log
E333=3.44).
Determination of mass transfer constants
through a hydrophilic membrane
The absorbances of drug solutions were lin-
early proportional to concentration in the range
studied. The permeability data, K, were calcu-
lated from the least-squares slopes of the ab-
sorbance-time data and the absorptivity using
the following relationship:
v added to a 50 ml centrifuge tube containing 4.5
--.-
,_G-Cl
tz -i$ C,F
where Co is the initial concentration of the drug
in the donor compartment, C, and C, are the
concentrations of the drug in the receptor com-
partment at time t2 and ti, respectively, Fis the
barrier area and V is the total receptor volume.
Determination of mass transfer constants
through a lipophilic membrane
The experimental measurements and the
evaluation of results for betamethasone and
menadione were performed according to the
work of Stricker [lo] for lipophilic drugs dif-
fusing through a lipoidal barrier. For nitrofur-
azone, phenylbutaxone and prednisone, eqn. ( 1)
was applied. In these cases, the amount of the
drug retained by the lipid phase of the barrier
was negligible.
Determination of partition coefficients
Octanol/buffer partition coefficients (P,,,)
A known volume of 0.025 Mphosphate buffer
(pH 7.0) saturated with octanol, containing the
drug, was added to a known volume of octanol
saturated with buffer. The mixture was then
shaken at 25 ‘C until the drug was equilibrated
between the two phases. After separation of the
layers by centrifugation, the drug in the aqueous
phase was determined and the octanol/buffer
partition coefficient was calculated.
IPM/buffer partition coefficients (&,,,)
The IPM/buffer partition coefficients of the
drugs were determined and previously
described.
IPM/buffer partition coefficients of the
drugs in the presence of coemulsifier (P,,)
Thirteen milliliters of buffer pH 7.0 were
ml of IPM and 2.5 ml of 1-butanol. The tube
was stoppered tightly and shaken until equilib-
rium was reached. After centrifugation the drug
concentration in the buffer was determined
spectrophotometrically.
IPM/buffer partition coefficients of
prednisone in the presence of different
amounts of coemulsifrer
Different volumes of 1-butanol (2.0,3.0 or 3.5
ml) were added to 4.5 ml of IPM. Then 13.0 ml
of a prednisone solution in buffer (5.0 x 10m4
M) was added. The concentration of predni-
sone in the aqueous phase was determined after
equilibrium was reached.
240

Release of menadione from a microemulsion TABLE 2

Mass transfer constants (K,,) of prednisone through the

The release of menadione from microemul-
hydrophilic membrane using microemulsions with differ-
sions during a period of 10 h was determined by ent amounts of butanol as the donor phase, and partition
measuring the permeation of this compound coefficients Pm, of the drug
through the hydrophilic membrane using the
microemulsion as the donor phase. Butanol K,,, P cm
(ml) (cm/min) X lo3

2.0 0.72 ?I0.05 5.4kO.l

RESULTS 2.5 0.56 f 0.03 6.4 + 0.2
3.0 0.41+ 0.02 7.9kO.3
3.5 0.33 f 0.02 9.2f0.3
(a) Partition coefficients

Table 1 shows the octanol/buffer (P,,), iso- TABLE 3

propyl myristate/buffer (PIPM) and isopropyl
Mass transfer constants of drugs dissolved in buffer through
myristate-butanol-buffer (P,,,) partition a hydrophilic or lipophilic membrane
coefficients of the five drugs examined. The
partition coefficients P,,, of the drugs were de- Dw K (cm/min) X lo3
termined using the same amounts of IPM, bu-
Hydrophilic Lipophilic
tanol and buffer as employed in the preparation
membrane membrane
of microemulsions.
In Table 2 the isopropyl myristate-butanol- Nitrofurazone 3.2fO.l 0.56 + 0.05
buffer partition coefficients of prednisone us- Phenylbutazone 1.4kO.l 0.90 + 0.05
Prednisone 1.950.1 1.6 fO.l
ing different amounts of butanol are listed. The
Betamethasone 2.5kO.l 2.1 fO.l
compositions are the same as those used for the Menadione 3.6kO.l 3.6 ?O.l
preparation of microemulsions.

(b) Drugs in aqueous solution: Mass transfer ble 3. The data were obtained from the least-
constants squares slopes of the linear portion (r> 0.99)
of the concentration uersus time curves.
The mass transfer constants of the drugs dis-
solved in buffer through either the hydrophilic (c) Drugs in microemulsions: Mass transfer
or the lipophilic membrane are reported in Ta- constants (K,,,,, &A

TABLE 1 The mass transfer constants of the drugs dif-

fusing from microemulsions through the hy-
Partition coefficients of drugs
drophilic and lipophilic membranes, respec-
Drug POCt P IPM P con tively, are shown in Table 4. The data were
obtained as previously described for drugs in
Nitrofurazone 1.8f 0.1 0.12 f 0.02 1.5+ 0.1
aqueous solution, where C, was the total con-
Phenylbutazone 5.3f 0.2 2.1 kO.2 4.5f 0.2
Prednisone 29 f 2 0.30 f 0.05 6.4+ 0.2 centration of the drug in the total volume of
Betamethasone 95 f 5 2.3 f0.3 30 k 2 microemulsion.
Menadione 160 f10 lOOf 180 +12 Table 4 also shows the mass transfer con-
Pti for octanol/buffer, PrpMfor isopropyl myristate/buffer, stants (Kcdc) of the drugs which were obtained
P COBfor isopropyl myristate-butanol-buffer partition by considering the continuous phase of the mi-
coefficients. croemulsion as the donor phase. The drug con-
 241

TABLE 4 microemulsions. The permeation coefficients

for drugs through the lipophilic membrane were
Mass transfer constants I&,, ( (cm/min) x 103) and I(_,,,,
( (cm/min) x 103) of the drug diffusing from microemul- linearly related to their octanol/buffer parti-
sions through a hydrophilic or a lipophilic membrane tion coefficients.
The results of the permeation studies pre-
Drug Hydrophilic Lipophilic sented in Tables 3 and 4 indicate that the in
membrane membrane
vitro release rates of the drugs from microe-
K Ul- K de K-n K cdc mulsions were lower than those from aqueous
solutions. The release of drug from microemul-
Nitrofurazone 1.8 fO.l 2.5 0.28 to.02 0.42
Phenylbutazone 0.70 k 0.05 1.5 0.39 f0.02 0.83
sions is governed by two main processes: trans-
Prednisone 0.56 kO.03 1.8 0.55 kO.05 1.7 fer of drug from the disperse to the continuous
Betamethasone 0.18 f 0.02 2.3 0.16 kO.01 2.0 phase, and diffusion of the drug through the
Menadione 0.050 k 0.005 3.8 0.041 k 0.005 3.4 membrane, from the continuous phase, to the
sink solution. Only the drug dissolved in the ex-
centrations in the continuous phase were cal- ternal aqueous phase is able to permeate
culated using PO,. These data were used as the through the hydrophilic membrane. Thus, the
initial concentrations, C,, in the equations pre- permeation of the drug through the membrane
viously used to determine K,,,,. will be initially governed by the drug concen-
tration in the external aqueous phase of the mi-
(d) Mass transfer constants (K,,,,) of croemulsion. The mass transfer constants
prednisone diffusing from microemulsions (K,,,) of the drugs through the hydrophilic
with different amounts of butanol through membrane were measured, taking the total con-
the hydrophilic membrane centration of the drug in the microemulsion as
the initial concentration. The different release
In Table 2 the mass transfer constants of rates from solutions and from microemulsion
prednisone through the hydrophilic membrane can be attributed to the partition of the drugs
from microemulsions with different amounts of between the dispersed oily droplets and the
1-butanol are given. continuous phase of the microemulsion.
The real partition of the drug between the
aqueous and the dispersed oil phase cannot be
DISCUSSION determined in microemulsions owing to the sta-
bility of the system. Therefore, the partition
Drugs with different hydrophobicities with- coefficients of the drugs between oil, buffer and
out dissociating groups were selected in order butanol (P,,,) were determined and used as an
to limit interactions with the anionic surfac- approximation for the partition in the microe-
tant AOT. Microemulsion components present mulsion. The approximate concentrations of the
in the external phase (not considering the drug in the external aqueous phase can then be
drug), and in particular butanol, may diffuse calculated using P,,,. After substituting these
through the membrane. To limit this diffusion, values in eqn. (1 ), the calculated permeation
a buffer containing butanol was used as the ac- coefficients (P&i,) can be obtained. The Kc,
ceptor medium in the permeation experiments. values are very similar to K values obtained with
The mass transfer constants of the drugs dis- aqueous drug solutions (Tables 3 and 4). The
solved in buffer, through a hydrophilic or lipo- linear correlation between log P,,, and log K,,
philic membrane, were measured to obtain ref- depicted in Fig. 1 may indicate the possibility
erence data for the permeation studies with of using the partition coefficient P,,, as a first
 tanol) and the correspon~g partition coeffi-
cients (logP,,) (Fig. 2).
Subsequently, the release of the drugs from
microemulsions through a lipophilic membrane
was studied. The permeation rate of a drug
through a lipophilic membrane is determined
by its partitioning between the buffer solution
and the membrane, the diffusion within the
membrane and the subsequent partitioning in
the sink solution.
The mass transfer constants of the drugs
(IL,,, Table 4) were first determined by using
‘ I 1 1
the total concentration of the drug in the mi-
-4.0 -3.5 -3.0 croemulsion as the initial concentration. The
log kmeas
drug concentrations of the continuous phase
Fig. 1. Logarithm of permeation coef~cien~ (log &,& of were calcula~d using P,,,; these data were then
drugs through a hydrophilic membrane versus log P,. Key:
used in eqn. ( 1) to obtain I&,,,. In this case also,
x , nitrofurazone; 0, phenylbutazone; A, prednisone; 0,
betamethasone; A, menadione. values were close to the K values obtained from
aqueous solutions and linearly related to oc-
tanol/buffer partition coefficients (Fig. 3).
1.0 -
Another aim of our work was to investigate
: the reservoir effect of the microemulsion. The
9 - release of menadione from the microemulsion
% was followed for several hours (Fig. 4). A
0.8- \
pseudo-zero-order release was obtained, as could
have been expected on the basis of the high par-
tition coefficient, PC,.
From the results so far obtained, it is con-

Fig. 2. Logarithm of prednisone permeation rate constants 21)-

(log Km,,) through a hydrophilic membrane using microe-

mulsions with different amounts of butanol versus log PC,,.
5
lf
m
-0
approximation of the drug distribution in the
1.0 -
microemulsion.
The release of prednisone from microemul-
sions using fixed quantities of IPM, buffer and
AOT but different amounts of butanol was then
studied. With increasing amounts of butanol the
t
permeability decreases and the partition coef- -3.2 -2.8 -2.4
ficient P,,, increases. A linear relationship was ‘WI kcalc

obtained between log Km*, (obtained from mi- Fig. 3. Log PM versus log I&._,=of drugs for a lipophilic
croemulsions with increasing aliquots of bu- membrane. Key: see Fig. 1.

2oo min
400 600
Fig. 4. Menadione release from buffer solution
0 1 and from microemulsion f 20 x 103; 0 1.
eluded that the partition coef~cien~ of a drug
between oil, water and cosurfactant can be used
to approximate its partition between the con-
tinuous and the disperse phase (including the
interphase in the disperse phase) of a microe-
mulsion. This approximation may not hold
when strong interactions of the drug with the
surfactant, either as single molecules or as mi-
celles, occur in the aqueous phase.
ACKNOWLEDGEMENT
This work was supported by grants from 60%
M.P.I.
243
REFERENCES
1 L.M. Prince, Microemulsions, Theory and Practice,
Academic Press, New York, NY, 1977, p. 91.
2 J. Ziegenmeyer and C. Ftihrer, Mikroemulsionen als
topische Arzneiform, Acta Pharma. Technol., 26
(1980) 273-275.
3 M.C. Martini, M.F. Bobin, H. Flandin, F. Caillaud and
J. Cotte, Role des microemulsions dans l’absorption
per&an&e de l’a-tocopherol, J. Pharm. Belg., 39
(1980) 348-354.
4 M.R. Gasco, M. Trotta and M. Castellano, Microe-
mulsioni con miristato di isopropile, Farmaco, Ed.
Prat., 41 (1986) 165-171.
(1.0~ 103; 5 H.E. Boddh and J.H. Joosten, A mathematical model
for drug release from a two-phase system to a perfect
sink, Int. J. Pharm., 26 (1985) 57-76.
6 T. Yo~uyana~, W.I. Higuchi and AH. Ghanem, The-
oretical treatment of diffusional transport into and
through an oil-water emulsion with an interfacial bar-
rier at the oil-water intefface, J. Pharm. Sci., 62 (1973)
40-43.
7 D. Friedman and S. Benita, A mathematical model for
drug release from o/w emulsions: application to con-
trolled release morphine emulsions, Drug. Dev. Ind.
Pharm., 13 (1987) 2067-2085.
8 A.M. Cazabat, D. Langevin and A. Pouchelon, Light-
scattering study of water-oil microemulsions, J. Col-
loid Interface Sci., 73 (1980) l-11.
9 J.M. Roe and B.W. Barry, Photon correlation spec-
troscopy of pharmaceutical system (sodium dodecyl
sulphate, sodium deoxycholate and chorpromazine
hy~oc~o~de micelles and polystyrene latices), Int.
J. Pharm., 14 (1983) 159-171.
10 H. Stricker, Pharmaceutical resorption in the gastro-
intestinal tract. II, Pharm. Ind., 35 (1973) 13-17.