Microemulsion-Based Vaginal Gel of Clotrimazole: Formulation, In Vitro
Evaluation, and Stability Studies
Yogeshwar G. Bachhav1and Vandana B. Patravale1,2
Received 24 June 2008; accepted 9 March 2009; published online 21 April 2009
the vaginal delivery of clotrimazole (CMZ). The solubility of CMZ in oils and surfactants was evaluated to
identify components of the microemulsion. The ternary diagram was plotted to identify the area of
microemulsion existence. Various gelling agents were evaluated for their potential to gel the CMZ
microemulsion without affecting its structure. The bioadhesive potential and antifungal activity of the CMZ
microemulsion-based gel (CMZ-MBG) was determined in comparison to the marketed clotrimazole gel
(Candid-V® gel) by in vitro methods. The chemical stability of CMZ in CMZ-MBG was determined as per
the International Conference on Harmonization guidelines. The CMZ microemulsion exhibited globule size
of 48.4 nm and polydispersity index of 0.75. Carbopol® ETD 2020 could successfully gel the CMZ
microemulsion without disturbing the structure. The CMZ-MBG showed significantly higher (P<0.05) in
that CMZ undergoes acidic pH-catalyzed degradation at all the storage conditions at the end of 3 months.
KEY WORDS: clotrimazole;microemulsion;microemulsion-basedvaginalgel;stabilitystudies;vaginaldelivery.
Vulvovaginal candidiasis is one of the most common
gynecological disorders. Approximately 75% of women experi-
ence vulvovaginalcandidiasis during theirlifeand about 40% to
50% of them suffer from multiple episodes (1,2). For the
treatment of vulvovaginal candidiasis, local treatment with
antifungal agents is a first resort. The local (vaginal) delivery
not only gives site-specific treatment but also avoids toxic side
effects of antifungal agents that are encountered on oral
administration. The most commonly prescribed treatment for
vaginal candidiasis has been the topical application of clotrima-
very effective locally and presents no major side effects (3).
Clotrimazole is available in several conventional dosage forms
such as creams, gels, pessaries, and ovules for vaginal applica-
tion. However, these conventional dosage forms do not offer
prolonged duration of action which compromises the efficacy of
the CMZ (4). Furthermore, poor water solubility of CMZ
(0.49 μg/ml) (5) also presents a hindrance for the local
availability of CMZ and limits the effective antifungal therapy.
In order to overcome these disadvantages, several delivery
strategies such as liposomes (4), microspheres (6), sustained-
release bioadhesive tablets (7), and polycarbophil gels (8) have
been proposed for the vaginal delivery of CMZ. However,
potential of microemulsions has not been explored for the
delivery of CMZ.
Microemulsions have demonstrated a great potential for
improving the systemic and local bioavailability of an array of
hydrophobic therapeutic agents (9–11). In view of this, the
solubilization of CMZ in microemulsions would improve its
vaginal availability. However, as discussed earlier, it is also
essential to have a dosage form which adheres to the vaginal
mucosa and increases the residence time of CMZ in vagina.
This functionality can be imparted by gelling of the CMZ
microemulsion using bioadhesive agent. The success of
mucoadhesive microemulsions has already been described in
the literature for the nasal delivery (12). Thus in the present
investigation, formulation of CMZ microemulsion-based gel
(CMZ-MBG) was attempted for vaginal delivery. The devel-
oped CMZ-MBG was evaluated for in vitro release, in vitro
bioadhesive time and in vitro antifungal activity. Furthermore,
the chemical stability of CMZ in the formulated gel was
evaluated as per the International Conference on Harmoniza-
tion (ICH) guidelines.
MATERIALS AND METHODS
Clotrimazole was kindly gifted by Cipla Pharmaceuticals
Ltd., Mumbai, India. Cremophore- EL (polyoxyl 35 castor oil),
Solutol HS 15 (macrogol 15 hydroxystearate; BASF India Ltd.,
Mumbai, India), Carbopol ETD-2020 (Noveon India Ltd.,
Mumbai, India), Gattefosse excipients such as Capryol 90
(propylene glycol monocaprylate), Plurol Oleique (polyglyceryl
oleate), Lauroglycol 90 (propylene glycol monolaurate), Lab-
racfac CC (caprylic–capric acid triglycerides), Labrafil 1944 CS
1530-9932/09/0200-0476/0#2009 American Association of Pharmaceutical Scientists
AAPS PharmSciTech, Vol. 10, No. 2, June 2009 (#2009)
1Department of Pharmaceutical Sciences and Technology, Institute
Chemical Technology, Matunga, Mumbai 400019, India.
2To whom correspondence should be addressed. (e-mail: vbpatravale@
(oleoyl macrogolglycerides), Methocel K4M (hydroproyl meth-
(sodium alginate; Anshul Agencies Ltd., Mumbai, India), and
Captex 8000 (glyceryl tricaprylate, Indchem International,
Mumbai, India) were received as gift samples. Methanol (high-
performance liquid chromatography (HPLC) grade), Tween 80,
citric acid anhydrous, disodium hydrogen phosphate, chloroc-
resol, dimethyl sulfoxide (DMSO), and benzyl alcohol (all AR
grade) were purchased from s.d. Fine Chemical Ltd., Mumbai,
India. Sabaraud dextrose agar was purchased from HiMedia
Ltd., Mumbai India.
Candid-V® gel (clotrimazole 2% w/w, Glenmark Phar-
maceuticals Ltd., Mumbai, India), a marketed vaginal gel of
clotrimazole was purchased from local market. Double-
distilled water was used whenever required.
The solubility of CMZ in various oils and surfactants was
determined by using shake-flask method (n=3). Briefly, an
excess amount of CMZ was added to each vial containing
5 ml of the selected vehicle, i.e., either oil or surfactant. After
sealing, the mixture was vortexed using a cyclomixer for
10 min in order to facilitate proper mixing of CMZ with the
vehicles. Mixtures were shaken for 72 h in an isothermal
shaker (Remi, Mumbai, India) maintained at 37±1°C.
Mixtures were centrifuged at 5,000 rpm for 15 min, followed
by filtration through membrane filter (0.45 μm, 13 mm, Pall
Life sciences, Mumbai, India). The concentration of CMZ in
the supernatant was determined by HPLC method.
HPLC Analysis of CMZ
The solubility of CMZ in various excipients was deter-
mined by a stability-indicating validated reverse-phase HPLC
method developed in-house. The HPLC apparatus consisted of
Jasco PU-2080 Plus Intelligent HPLC pump (Jasco, Japan)
equipped with a Jasco UV-2075 Intelligent UV/VIS detector
(Jasco, Japan), a Rheodyne 7725 injector (Rheodyne, USA), a
Jasco Borwin Chromatography Software (version 1.50) integra-
tor software, and a Hi-Q-Sil RP-18 (4.6×250 mm and 10-μm
particle size) column. The mobile phase consisted of a mixture
of methanol: dipotassium hydrogen phosphate (0.025 M) buffer
(75:25 v/v) at a flow rate of 1.5 ml/min that led to retention time
of 12.5 min whendetection was carried out at 254 nm.The assay
was linear (r2=0.999) in the concentration range 10–250 μg/ml
with the lowest detection limit of 1.33 μg/ml of CMZ. The
method was validatedwith respect to accuracy and interday and
intraday precision as per ICH guidelines and the relative
standard deviation was less than 2% in both the cases.
An oil titration method was employed in the present
investigation to construct phase diagrams (13). Briefly, mixtures
of the double-distilled water with Cremophore EL were
prepared at ratios (% w/w) of 9:1, 8:2, 7:3, 6:4, 5:5, 4:6, 3:7, 2:8,
and 1:9 into different vials. A small amount of Capryol 90 in
0.5% (w/w) increments was addedinto thevials. Following each
addition, the mixtures in vials were vortexed for 2 to 3 min and
were allowed to equilibrate at 25°C for 30 min. After
equilibration, the mixtures were examined visually for phase
separation, transparency, and flow properties. In addition, the
mixtures were observed through crossed polarizers (fabricated
in-house by using polarizing lenses, Nikkon, Japan) for deter-
mining the optical isotropy of the systems. The point at which
the mixture became turbid or showed signs of phase separation
was considered as the end point of the titration. The area of
microemulsion existence was determined and denoted as ME.
Formulation of Microemulsion
From the phase diagrams, suitable composition was chosen
for further studies. The composition is shown in Table I. Briefly,
CMZ (200 mg) was dissolved in Capryol 90 (14.0 g) by using
overhead stirrer at 1,000 rpm. To this solution, Cremophore EL
(43.5 g), benzyl alcohol (2.0 g), and chlorocresol (0.1 g) were
added and the mixture was stirred further to yield a homoge-
nous solution. To this solution, water (38.4 g) was added and
stirred further to yield microemulsion.
Globule Size Analysis of the Microemulsion
The average globule size and polydispersity index of the
CMZ microemulsion were determined in duplicate by the
photon correlation spectroscopy (Beckman Coulter N4 plus,
Wipro, India). Measurements were carried at an angle of 90°
at 25°C. Microemulsion was diluted with double-distilled
water to ensure that the light-scattering intensity was within
the instrument’s sensitivity range. Double-distilled water was
filtered through 0.45-μm membrane filters (Pall Life Sciences,
Mumbai, India) prior to globule size determination.
Formulation of Microemulsion-Based Gel of CMZ
Various gelling agents, namely, sodium alginate (Manugel
DMB), hydroxypropyl methylcellulose (Methocel K4 M), and
Carbopol® ETD 2020, were evaluated for their ability to gel
CMZ microemulsion. Briefly, the nonaqueous part of the
microemulsion was prepared as described above (“Formulation
of Microemulsion”); gelling agent was dispersed/dissolved in
water by using overhead stirrer at 1,000 rpm. Aqueous part was
mixed with nonaqueous part by stirring. The suitable gelling
agent was selected on the basis of compatibility with micro-
emulsion structure, feel, and ease of spreadability. The opti-
mized composition of CMZ-MBG is shown in Table II.
Table I. Composition of CMZ Microemulsion
IngredientContent (% w/w)
Water to make (g)
477Microemulsion-Based Vaginal Gel of Clotrimazole: Formulation, In Vitro Evaluation, and Stability Studies
Characterization of the CMZ-MBG
Determination of CMZ Content, pH, and Spreadability
For determination of drug content, about 1 g of the gel was
was diluted appropriately and analyzed by the HPLC method
described earlier. The spreadability of the gel was determined
using the following technique: 0.5 g gel was placed within a circle
of 1-cm diameter premarked on a glass plate over which a second
upper glass plate for 5 min. The increase in the diameter due to
determined using Equip-tronic Digital pH meter Model EQ 610,
standardized using pH 4.0 and 7.0 standard buffers before use.
Rheological Studies on the MBG
Brookfield Synchro-Lectric Viscometer (Model RVT)
with helipath stand was used for rheological studies. The
sample (30 g) was placed in a beaker and was allowed to
equilibrate for 5 min before measuring the dial reading using a
T–C spindle at 0.5, 1, 2.5, and 5 rpm. At each speed, the
corresponding dial reading on the viscometer was noted. The
spindle speed was successively lowered and the corresponding
dial reading was noted. The measurements were carried in
duplicate at ambient temperature. Direct multiplication of the
dial readings with factors given in the Brookfield viscometer
catalog gave the viscosity in centipoises.
In Vitro Bioadhesion Study
The bioadhesive potential of the CMZ-MBG was evaluat-
ed in comparison with the marketed clotrimazole gel (Candid-
V® gel) by an in vitro method reported by Nakamura et al. (14).
Briefly, an agar plate (1% w/w) was prepared in pH 4.5 citrate
phosphate buffer. Test sample of 50 mg was placed at the center
of plate. After 5 min, the agar plate was attached to a US
Pharmacopeia disintegration test apparatus (Fig. 1) and moved
up and down in pH 4.5 citrate phosphate buffer at 37±1°C. The
point and was out of the solution at the highest point. The
residence time of the test samples on the plate was noted
visually. The experiments were performed in triplicate.
In Vitro Dissolution
In vitro release profiles of CMZ-MBG and Candid-V®
were studied using modified USP XXIII apparatus I at 37±
0.5° C with a rotating speed of 25 rpm in buffer pH 4.5 citrate
phosphate buffer as a dissolution medium. A watch dish
containing 1.0 g of the developed formulation was tightly
secured with a stainless steel wire screen (350 µ mesh size
sinker). The dish was then dipped in 500 ml pH 4.5 citrate
phosphate buffer, contained in a vessel of USP dissolution test
apparatus. During the study, 2 ml of aliquots were removed at
predetermined time intervals (0.5, 1, 2, 3, 4, 6, 8, 10, and 12 h)
from the dissolution medium and replaced with fresh media.
The amount of CMZ released in the dissolution medium was
determined by a HPLC methoddescribedearlier. Samples were
filtered through 0.45 µ nylon membrane filter.
In Vitro Antifungal Activity
Antifungal activity of CMZ-MBG, Candid-V® gel, and
CMZ standard (CMZ dissolved in DMSO) was evaluated
against Candida albicans ATCC 10231 by using a cup plate
method. Briefly, the concentration of C. albicans ATCC 10231
in inocula was equivalent to 5×1015CFU/ml. CMZ-MBG,
Candid-V® gel (500 mg each), and 1 ml of CMZ dissolved in
DMSO (10 mg/ml) was added to agar plate and plates were
kept in the darkconditions at roomtemperature for 48h. After
incubation, the mean zone of inhibition was recorded for all
the test samples (n=3).
Chemical stability of CMZ in CMZ-MBG was assessed
at various storage conditions viz. 25°C/60% relative humidity
(RH), 30°C/65% RH, and 40°C/75% RH for a period of
3 months. CMZ-MBG was packed in 10-g aluminum oint-
ment tubes. Samples (n=3) were removed at 0, 30, 60, and
90 days and were assessed for CMZ content by a stability-
indicating HPLC method described earlier. The statistical
significance of differences in the data was analyzed utilizing
analysis of variance followed by Bonferroni’s test (GraphPad
InStat Demo Version). Differences were considered statisti-
cally significant at P<0.05.
RESULTS AND DISCUSSION
The results of the solubility studies are shown in
Table III. It is evident from Table III that the Capryol 90
exhibited the highest solubilizing potential for the CMZ as
compared to the other oils. Among the various surfactants
Table II. Composition of CMZ-MBG
IngredientContent (% w/w)
Water to make (g)
Fig. 1. Apparatus used for in vitro bioadhesion study
478Bachhav and Patravale
used in the study, Labrasol exhibited the highest solubilizing
potential for CMZ followed by Solutol HS 15, Cremophore
EL, and Tween 80 (Table III). However, Labrasol has poor
emulsification ability for Capryol 90 as compared to the other
surfactants (15). Among the surfactants employed in the
study, Cremophor EL exhibited excellent emulsification
ability for Capryol 90 (15) and fairly good solubilizing
potential for the CMZ. Hence, Cremophore EL was selected
for the further studies.
It is reported that nonionic surfactants alone can yield
microemulsion without help of cosurfactant (9–11). The phase
diagram of Cremophore EL-Capryol 90-water system is shown
in Fig. 2. Black region in the figure indicates microemulsion
region (ME region) and white region is non-ME region. It is
evident from the figure that Cremophore alone could give
considerable microemulsification region (>30%). White circle
in the black region of Fig. 2 indicates ME composition selected
for formulation. Selection of this ME composition was based
on solubility of CMZ in Capryol 90 and amount of Cremophor
EL required for emulsification to produce a stable micro-
emulsion. The selected microemulsion system was composed
of maximum amount of water possible. The microemulsion for
further studies was selected from the phase diagram which had
globule size of 48.4 nm and polydispersity index of 0.75. The
incorporation of CMZ did not have considerable influence on
the globule size of the microemulsion.
Formulation and Characterization of the MBG
Various gelling agents such as sodium alginate, hydrox-
ypropyl methylcellulose, and Carbopol® ETD 2020 were
evaluated for the gelling of CMZ microemulsion. It was
observed that sodium alginate affected the structure of the
microemulsion and resulted in separation of oily phase. This
observation couldbeattributed tothatfactthatsaltslike sodium
alginate can affect the structure of the microemulsion (9–11).
Hydroxypropyl methylcellulose was unable to yield viscosity
desirable for the gel formulations. Only Carbopol® ETD 2020
couldyieldcleargel withoutdisturbingthe microstructureofthe
CMZ microemulsion. Furthermore, Carbopols are known to
have mucoadhesive properties and have been used in the
formulation vaginal delivery systems (7,8,16). Hence, Carbo-
pol® ETD 2020 was selected for the formulation of MBG.
The CMZ content of the MBG and Candid-V® gel was
found to be 98.4±3.2% and 99.6±0.8%, respectively. The pH
value of CMZ-MBG was 4.52 which is equivalent to the vaginal
pH; for candid-V®, pH value was 6.8. Spreadability is an
important property of topical formulation from patient compli-
ance point of view. The diameter for CMZ-MBG and Candid-
V® was found to be 7.2 and 6.20 cm, respectively. High
spreadability value of CMZ-MBG compared to Candid-V
indicates better spreading ability at the site of application. Both
CMZ-MBG and Candid-V® showed pseudoplastic behavior
andtheviscosity valuesofCMZ-MBG andCandid-V®at 5 rpm
were 9.0×106and 7.8×106mPa s, respectively.
Table III. Solubility of CMZ in Various Oils and Surfactants (n=3)
Excipient Solubility (mg/ml)
Labrafil 1944 CS
Fig. 2. Ternary-phase diagram of Cremophore EL-Capryol 90-Water
Table IV. Results of In vitro Bioadhesion Studies (n=3)
In vitro bioadhesion time (min)
*P<0.05 as compared to Candid-V® gel
Fig. 3. In vitro dissolution profile of CMZ formulations (n=3)
479Microemulsion-Based Vaginal Gel of Clotrimazole: Formulation, In Vitro Evaluation, and Stability Studies
In Vitro Bioadhesion Study
The bioadhesive potential of CMZ-MBG and commercial
formulation (Candid-V® gel) was evaluated by in vitro method.
The results of the study are shown in Table IV. The CMZ-MBG
showed significantly higher retention time as compared to
Candid-V® gel (P<0.05). This clearly indicates that the CMZ-
MBG may have higher residence time in vagina as compared to
Candid-V® gel. The increased bioadhesivity of CMZ-MBG can
be attributed to the presence of Carbopol.
In Vitro Dissolution
In vitro release profile of CMZ-MBG and Candid-V®
gel is shown in Fig. 3. More than 85% of CMZ was released
over the period of 12 h from CMZ-MBG and it followed first-
order release kinetics. Candid-V gel® showed maximum 70%
release of CMZ up to 12 h. The in vitro release pattern of
CMZ-MBG and Candid-V® gel was equivalent up to 3 h.
After this initial phase, Candid-V® gel produced higher
release of CMZ up to 6 h and it was constant at the end of
12 h. CMZ-MBG provided controlled release of CMZ up to
12 h. The difference between the release pattern of MBG and
Candid-V® gel was nonsignificant as determined by F2test
(F2=61.99 with standard error of 7.049).
In Vitro Antifungal Activity
The results of antifungal studies are shown in Table V. It
is evident that CMZ-MBG showed higher antifungal activity
as compared to the marketed Candid-V® gel and CMZ
standard (P<0.01). The enhanced in vitro antifungal activity
of CMZ-MBG may be attributed to enhanced penetration of
oil globules containing CMZ through fungal cell walls to
inhibit ergosterol synthesis.
The results of stability studies are shown in Table VI. It
is evident from the table that CMZ showed a significant
degradation (P<0.05) at all the storage conditions at the end
of 3 months. This observation was totally unexpected. The
rate of degradation increased with the increase in the
temperature. Hence, at 40°C/75% RH, around 38% of
CMZ was degraded at the end of the 3 months. The
chromatogram of the sample (stored at 40°C/75% RH) at
the end of the third month is shown in Fig. 4 and it clearly
shows the well-resolved degradation product of the CMZ.
Interestingly, this chromatogram is similar to the chromato-
gram obtained after forced degradation of CMZ in 1 N HCl
(Fig. 5). This clearly indicates that degradation of CMZ in
MBG is due to the acidic pH of the formulation. The
acidic pH of the MBG could be attributed to the presence
of the free fatty acids (such as caprylic acid) in the Capryol
It was observed that commercial formulation of CMZ
(Candid-V® gel) has pH value of 6.81 and it claims stability
of up to 1.5 years. This corroborates the inferences drawn
about the acid-catalyzed degradation of CMZ.
Our preliminary investigations on the stabilization of the
CMZ in CMZ-MBG indicated that the increase in the pH of
the gel results in the loss of transparency and also disturbs the
Table V. Antifungal Activity of Various Samples Against C. albicans
ATCC 10231 (n=3)
FormulationZone of inhibition (mm)
CMZ-MBG showed significantly higher in vitro antifungal activity
*P<0.05 as compared to CMZ-MBG
Table VI. Chemical Stability of CMZ in CMZ-MBG During Stability
% CMZ content in gel (±SD)
25°C/60% RH 30°C/60% RH40°C/75% RH
Fig. 4. Chromatogram of the CMZ-MBG subjected to 40°C/75% RH
at the end of 3 months
Fig. 5. Chromatogram of forced degradation of CMZ in acidic con-
ditions (1 N HCl)
480Bachhav and Patravale
structure of the microemulsion (data not shown). Hence, it Download full-text
may be necessary to reformulate the developed MBG. The
future efforts would be directed towards identifying an oily
phase that preserves the integrity of CMZ on long-term
storage and has good solubilizing potential for CMZ.
Nonetheless, this investigation clearly indicates that MBG
could be a viable alternative to the conventional vaginal
The microemulsion-based gel could be successfully
developed for the vaginal delivery of clotrimazole. The
developed gel showed promising in vitro performance with
respect to bioadhesivity and antifungal activity. However,
CMZ showed a considerable degradation on long-term
storage in the developed microemulsion-based gel which
was attributed to the pH of the formulation.
YGB thanks the University Grants Commission, New
Delhi India for the financial support. The authors are
thankful to Cipla Pharmaceuticals, BASF, Indchem Interna-
tional, Noveon India, Anshul Agencies and Colorcon Asia
Pvt. Ltd. for the gift samples of the drug and excipients.
Authors would like to acknowledge Mr. Abhijit Date for his
help in the preparation of the manuscript and also for the
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481Microemulsion-Based Vaginal Gel of Clotrimazole: Formulation, In Vitro Evaluation, and Stability Studies