The AAPS Journal 2004; 6 (3) Article 26 ([Link]

Optimization of Chlorphenesin Emulgel Formulation

Submitted: December 31, 2003; Accepted: May 17, 2004; Published: October 11, 2004.
Magdy I. Mohamed1
1Department of Pharmaceutics, Faculty of Pharmacy, Cairo University, Cairo, Egypt

ABSTRACT Both oil-in-water and water-in-oil emulsions are extensively

used for their therapeutic properties and as vehicles to deliv-
This study was conducted to develop an emulgel formulation
er various drugs to the skin.3 Emulsions possess a certain
of chlorphenesin (CHL) using 2 types of gelling agents:
degree of elegance and are easily washed off whenever
hydroxypropylmethyl cellulose (HPMC) and Carbopol 934.
desired. They also have a high ability to penetrate the skin. In
The influence of the type of the gelling agent and the concen-
addition, the formulator can control the viscosity, appear-
tration of both the oil phase and emulsifying agent on the drug
ance, and degree of greasiness of cosmetic or dermatological
release from the prepared emulgels was investigated using a
emulsions. Oil-in-water emulsions are most useful as water-
23 factorial design. The prepared emulgels were evaluated for
washable drug bases and for general cosmetic purposes,
their physical appearance, rheological behavior, drug release, while water-in-oil emulsions are employed more widely for
antifungal activity, and stability. Commercially available the treatment of dry skin and emollient applications.4
CHL topical powder was used for comparison. All the pre-
pared emulgels showed acceptable physical properties con- Gels for dermatological use have several favorable properties
cerning color, homogeneity, consistency, spreadability, and such as being thixotropic, greaseless, easily spreadable, eas-
pH value. They also exhibited higher drug release and anti- ily removable, emollient, nonstaining, compatible with sev-
fungal activity than the CHL powder. It was found that the eral excipients, and water-soluble or miscible.5
emulsifying agent concentration had the most pronounced Emulgels are emulsions, either of the oil-in-water or water-
effect on the drug release from the emulgels followed by the in-oil type, which are gelled by mixing with a gelling agent.
oil phase concentration and finally the type of the gelling They have a high patient acceptability since they possess the
agent. The drug release from all the emulgels was found to previously mentioned advantages of both emulsions and
follow diffusion-controlled mechanism. Rheological studies gels. Therefore, they have been recently used as vehicles to
revealed that the CHL emulgels exhibited a shear-thinning deliver various drugs to the skin.6-8 In the local Egyptian
behavior with thixotropy. Stability studies showed that the market, 2 emulgels are available: Voltaren emulgel (Novartis
physical appearance, rheological properties, drug release, and Pharma, Basle, Switzerland), containing diclofenac diethy-
antifungal activity in all the prepared emulgels remained lamine, and Miconaz-H emulgel (Medical Union
unchanged upon storage for 3 months. As a general conclu- Pharmaceuticals, Abu-Sultan, Ismailia, Egypt), containing
sion, it was suggested that the CHL emulgel formulation pre- miconazole nitrate and hydrocortisone.
pared with HPMC with the oil phase concentration in its low The aim of this work was to develop an emulgel formulation
level and emulsifying agent concentration in its high level of CHL using 2 types of gelling agents: Carbopol 934 and
was the formula of choice since it showed the highest drug HPMC. The influence of the type of the gelling agent and the
release and antifungal activity. concentration of both the oil phase and the emulsifying agent
on the release of the drug from the prepared emulgels was
investigated using 23 factorial design. The rheological prop-
KEYWORDS: chlorphenesin, emulgel, factorial design. erties and antifungal activity of the prepared emulgels were
also evaluated.
INTRODUCTION
Several antifungal agents are available on the market in differ- MATERIALS AND METHODS
ent topical preparations (eg, creams, ointments, and powders Materials
for the purpose of local dermatological therapy). One of these
The following materials were used in this study: CHL
antifungal agents is chlorphenesin (CHL), which has both anti-
(Chemical Industries Development, Cairo, Egypt); Carbopol
fungal and antibacterial properties. It is applied locally in mild
934 (Goodrich Chemical Co, Cleveland, Ohio); HPMC 2910,
uncomplicated dermatophyte and other cutaneous infections.1,2
4000 cps (Tama, Tokyo, Japan); Tween 20 and Span 20 (Union
Corresponding Author: Magdy I. Mohamed, Department Carbide, Houston, TX); methyl and propyl parabens
of Pharmaceutics, Faculty of Pharmacy, Cairo University, (Mallinckrodt Specialty Chemicals Co, Paris, KY); light liquid
Cairo, Egypt. Tel: 023597240 Fax: 5320005 Email: paraffin, propylene glycol, triethanolamine (TEA), and ethyl
MagdyMohamed1@[Link]. alcohol (El-Nasr Co for Chemicals and Pharmaceuticals,
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 The AAPS Journal 2004; 6 (3) Article 26 ([Link]

Table 1. Factors and Levels for the 23 Factorial Design Table 2. Qualitative Composition of Chlorphenesin
Factors Levels Emulgel Formulations
+ HPMC Composition†
(A) Gelling agent type
- Carbopol Combination* Formulation A B C
+ 7.5% (1) F1 - - -
(B) Liquid paraffin concentration
- 5% A F2 + - -
+ 2.5% B F3 - + -
(C) Emulsifying agent concentration
- 1.5% AB F4 + + -
C F5 - - +
Cairo, Egypt); cellulose membrane with a molecular weight
AC F6 + - +
cutoff point of 10 000 (Spectrum Medical Industries Inc, CA);
BC F7 - + +
and Candida albicans NCTC 3179 (clinical isolate grown at
ABC F8 + + +
25°C for 24 hours on Sabouraud’s agar).
*A, Gelling agent type, B, liquid paraffin concentration, C, emulsifying
agent concentration
Experimental Design †Factor at low level, +, factor at high level.

Eight CHL emulgel formulations were prepared according to obtained emulsion was mixed with the gel in 1:1 ratio with
a 23 factorial design employing the qualitative factors and gentle stirring to obtain the emulgel.
levels shown in Tables 1 and 2.

Physical Examination
Preparation of CHL Emulgel Formulations
The prepared emulgel formulations were inspected visually
The composition of CHL emulgel formulations is shown in
for their color, homogeneity, consistency, spreadability, and
Table 3. The gel in formulations F1, F3, F5, and F7 was pre-
phase separation. The pH values of 1% aqueous solutions of
pared by dispersing Carbopol 934 in purified water with con-
the prepared emulgels were measured by a pH meter (CG
stant stirring at a moderate speed; then the pH was adjusted
820, Schott Gerate GmbH, Hofheim, Germany).
to 6 to 6.5 using TEA. In formulations F2, F4, F6, and F8, the
gel was prepared by dispersing HPMC in heated purified
water (80°C), and the dispersion was cooled and left Rheological Studies
overnight. The oil phase of the emulsion was prepared by
The viscosity of the different emulgel formulations was deter-
dissolving Span 20 in light liquid paraffin while the aqueous
mined at 25°C using a cone and plate viscometer with spindle
phase was prepared by dissolving Tween 20 in purified
52 (Brookfield Engineering Laboratories, model HADV-II,
water. Methyl and propyl parabens were dissolved in propy-
Middleboro, MA) and connected to a thermostatically con-
lene glycol whereas CHL was dissolved in ethanol, and both
trolled circulating water bath (Polyscience, model 9101,
solutions were mixed with the aqueous phase. Both the oily
Niles, IL). The recorded viscosities are collected in Table 4,
and aqueous phases were separately heated to 70° to 80°C;
then the oily phase was added to the aqueous phase with con- and the entire rheograms are shown in Figures 1 and 2.
tinuous stirring until cooled to room temperature. The
Table 3. Quantitative Composition of Chlorphenesin Emulgel Formulations (% wt/wt)
Ingredient F1 F2 F3 F4 F5 F6 F7 F8
Chlorphenesin 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5
Carbopol 934 1 1 1 1
HPMC* 2.5 2.5 2.5 2.5
Liquid paraffin 5 5 7.5 7.5 5 5 7.5 7.5
Tween 20 0.6 0.6 0.6 0.6 1 1 1 1
Span 20 0.9 0.9 0.9 0.9 1.5 1.5 1.5 1.5
Propylene glycol 5 5 5 5 5 5 5 5
Ethanol 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5
Methyl paraben 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03
Propyl paraben 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01
Purified water to 100 100 100 100 100 100 100 100
*HPMC indicates hydroxypropylmethyl cellulose.

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 The AAPS Journal 2004; 6 (3) Article 26 ([Link]

Table 4. Viscosities (in Poise) of Chlorphenesin Emulgel Stability Studies

Formulations at Low and High Rates of Shear The prepared CHL emulgel formulations were stored away
Formulation η min* η max† Formulation η min* η max† from light in high-density polyethylene bottles at 40°C and
F1 6410 1200 F2 66.84 27.55 4°C for 3 months. After storage, the samples were tested for
their physical appearance, pH, rheological behavior, drug
F3 6330 1060 F4 96.73 27.95
release, and antifungal activity.
F5 7610 1220 F6 54.26 19.97
F7 6680 1090 F8 57.41 17.44
*Viscosity at low rate of shear. RESULTS AND DISCUSSION
†Viscosity at high rate of shear.
Physical Examination
In Vitro Release Studies The prepared CHL emulgel formulations were white viscous
A glass cup with a cross-sectional area of 7.5 cm2was filled creamy preparations with a smooth and homogeneous
with 3 g of the emulgel, covered with a cellulose membrane, appearance. They were easily spreadable with acceptable
sealed with a rubber band, and inverted under the surface of bioadhesion and fair mechanical properties. The pH values of
500 mL of phosphate buffer of pH 5.5 at 37°C ± 0.5°C in a all the prepared formulations ranged from 6.3 to 6.5, which
United States Pharmacopeia (USP) dissolution tester is considered acceptable to avoid the risk of irritation upon
(Pharma Test, PTW, Type II, Hainburg, Germany) with a application to the skin.11,12
paddle speed of 50 rpm. Such assembly has been validated in
a previous study.9 Aliquots were withdrawn at specified time Rheological Studies
intervals over a 3-hour period and immediately replaced with
fresh dissolution medium. The drug content in the withdrawn Figures 1 and 2 show the entire rheograms (shear stress vs
samples was determined spectrophotometrically at 226 nm shear rate) of CHL emulgel formulations. As seen in the fig-
using a UV spectrophotometer (Shimadzu UV 240, Kyoto, ures, all the prepared emulgel formulations exhibited a shear-
Japan). The CHL topical powder commercially available in thinning behavior since the viscosity (the slope of the curve)
the local market was used for comparison. The in vitro decreased with increasing the shear rate. As the shear stress is
release profiles of CHL from its emulgel formulations are increased, the normally disarranged molecules of the gelling
represented in Figure 3. Statistical and kinetic treatments of material are caused to align their long axes in the direction of
the release data of the drug from the different emulgel formu- flow. Such orientation reduces the internal resistance of the
lations were performed, and the results are compiled in material and hence decreases the viscosity. The figures also
Tables 5 and 6, respectively. show that all CHL emulgel formulations possessed thixotrop-
ic behavior, where the down curve was displaced with regard
to the up curve, showing at any rate of shear on the down curve
Microbiological Assay a lower shear stress than it had on the up curve; a hysteresis
Ditch plate technique was used. It is a technique used for loop was formed between the 2 curves. Thixotropy, or time-
evaluation of bacteriostatic or fungistatic activity of a com- dependent flow, occurs because the gel requires a finite time to
pound. It is mainly applied for semisolid formulations.10 rebuild its original structure that breaks down during continu-
Previously prepared Sabouraud’s agar dried plates were ous shear measurements.5 It is noteworthy that thixotropy is a
used. Three grams of the emulgel were placed in a ditch cut desirable characteristic in pharmaceutical preparations, both in
in the plate. Freshly prepared culture loops were streaked engineering design and consumer application, in order to
across the agar at a right angle from the ditch to the edge of deliver an initially thick product as a thinner, easily spreadable
the plate. The commercial CHL powder was used for com- material. These findings are in agreement with Abd El-Bary et
parison. Control plates containing plain emulgel bases were al, who had prepared chloramphenicol emulgel using
also prepared. After incubation for 18 to 24 hours at 25°C, Carbopol 940 as the gel-forming material.6 The recorded vis-
the fungal growth was observed and the percentage inhibi- cosities of the different CHL emulgel formulations at both low
tion was measured as follows: and high shear rates are collected in Table 4, which showed
that the Carbopol-based formulations (F1, F3, F5, and F7) pos-
% inhibition = L2 / L1 × 100 (1) sessed considerably higher viscosities than the HPMC-based
formulations (F2, F4, F6, and F8).
where L1 = total length of the streaked culture, and L2 =
length of inhibition. The results of this experiment are com- In Vitro Release Studies
piled in Table 7. The in vitro release profiles of CHL from its various emulgel
formulations are represented in Figure 3. It was observed that
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 The AAPS Journal 2004; 6 (3) Article 26 ([Link]

Figure 1. Rheograms of carbopol-based chlorphenesin emulgel formulations (mean ± SD, n = 3): (A) formulation F1, (B)
formulation F3, (C) formulation F5, and (D) formulation F7.
all the formulations had become liquefied and diluted at the Carbopol emulgel formulations as observed in Table 4. It may
end of the experiment, indicating water diffusion through the also be due to the entrapment of the drug in the network struc-
membrane. In general, it can be observed from Figure 3 that ture of Carbopol 934.13 Contrary to F6 and F5 formulations, F4
the release of the drug from its all emulgel formulations was and F3 showed the lowest drug release. In formulations F4 and
higher than its release from its commercial powder. The F3, liquid paraffin is present in its high level, while the emul-
release of the drug from its emulgel formulations can be sifying agent is in its low level. Formula F8, containing both
ranked in the following descending order: F6 > F5 > F8 > F2 > liquid paraffin and the emulsifying agent in their high levels,
F7 > F1 > F4 > F3, where the amounts of the drug released after exhibited greater drug release than formula F2, containing
3 hours were 39.44%, 31.32%, 28.91%, 27.28%, 26.64%, both liquid paraffin and the emulsifying agent in their low lev-
25.08%, 24.33%, and 23.1%, respectively. However, only els. This finding indicated that the enhancing effect of the
18.1% of the drug was released from the commercially avail- emulsifying agent on the drug release was more pronounced
able powder after the same period of time. Thus, the greatest than the lowering effect of liquid paraffin on the drug release.
drug release was observed with formulations F6 and F5. This The same observation was found in F7 and F1 formulations.
finding may be due to the presence of liquid paraffin in its low Although F5 is Carbopol based, it showed a greater drug
level and the emulsifying agent in its high level in both such release than F8, which is HPMC based. This finding is due to
formulations, which leads to an increase in the hydrophilicity the lower liquid paraffin content in formula F5 than in formu-
of the emulgel, which, in turn, facilitates penetration of the la F8. The same is true for F1 and F4. This finding proved that
release medium into the emulgel and diffusion of the drug the effect of liquid paraffin in decreasing the drug release
from the emulgel. This finding was in agreement with Abd El- from the emulgel was more predominant than the enhancing
Bary et al,6 who proved that the presence of liquid paraffin led effect of HPMC on the drug release. Thus the 3 studied fac-
to retardation of chloramphenicol release from its emulgel tors can be arranged according to their effect on the drug
formulation. The lower drug release from formula F5, which release from the emulgel formulations as follows: the emulsi-
is Carbopol-based, than the drug release from formula F6, fying agent concentration > liquid paraffin concentration >
which is HPMC-based, may be due to the higher viscosity of the gelling agent type.
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 The AAPS Journal 2004; 6 (3) Article 26 ([Link]

Figure 2. Rheograms of HPMC-based chlorphenesin emulgel formulations (mean ± SD, n = 3): (A) formulation F2, (B)
formulation F4, (C) formulation F6, and (D) formulation F8.
and IBC), it is obvious from Table 5 that the most important
interaction took place between liquid paraffin concentration
and the emulsifying agent concentration (IBC), and such
interaction was significant at P ≤ .25.
The drug release data were analyzed according to zero- and
first-order kinetics as well as diffusion- controlled mecha-
nism using linear regression analysis. The results, as shown
in Table 6, revealed that the drug release from the CHL emul-
gel formulations followed Higuchi diffusion model15 with a
correlation coefficient ranging from 0.9924 to 0.9992, which
means an excellent model fit. This finding indicates that the
rate-controlling stage in the release process was diffusion of
the dissolved drug through the gel network to the external
medium, which, in turn, explains why the amount of the drug
Figure 3. Release profiles of chlorphenesin from its emul-
released did not exceed 39.44%.
gel formulations (mean ± SD, n = 3).
Table 5 shows the results of evaluation of the factorial design
Microbiological Assay
using Yates analysis of variance.14 These results demonstrat-
ed that the 3 main effects (EA, EB, and EC) were statistical- The use of control plates showed that the plain emulgel bases
ly significant at P ≤ .05. The most important factor for were microbiologically inert toward the tested Candida albi-
enhancing the drug release was the emulsifying agent con- cans strain. The antifungal activity of CHL in its different
centration followed by liquid paraffin concentration and then emulgel formulations as well as in its commercially available
the gelling agent type. This was in accordance with the pre- powder form are shown in Table 7. Percentage inhibition was
vious finding. Regarding the primary interactions (IAB, IAC, taken as a measure of the drug antifungal activity. The emul-
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 The AAPS Journal 2004; 6 (3) Article 26 ([Link]

Table 5. Statistical Analysis of the Main Effects (E) and Interactions (I) on the Percentage Chlorphenesin Released After 3
Hours (Q) From Its Emulgel Formulations
E or I Response (Q) Effect Mean Square df F
EA 25.28 3.455 23.87 1 4.82†
EB 21.1 -5.035 50.7 1 10.24†
EC 29.32 6.63 87.91 1 17.76†
I AB 22.33 -1.705 5.81 1 1.17
I AC 37.44 1.74 6.06 1 1.22
I BC 24.64 -2.57 13.21 1 2.67
I ABC 26.91 -1.22 2.98 1 0.6
Error* = 4.95 3
*Error mean square based on AB, AC, and ABC interactions.
† P ≤ .05

Table 6. Kinetic Treatment of the Release Data of Chlorphenesin From Its Emulgel Formulations

Correlation Coefficient Release Rate

Mechanism of Constant
Formulation Zero Order First Order Diffusion Release ([Link]-1/2)*
F1 0.9787 0.9845 0.9986 Diffusion 1.8854
F2 0.9863 0.9911 0.9992 Diffusion 1.9263
F3 0.9914 0.9945 0.9965 Diffusion 1.8746
F4 0.9804 0.9861 0.9992 Diffusion 1.8652
F5 0.9883 0.9918 0.9927 Diffusion 2.1168
F6 0.9873 0.9917 0.9924 Diffusion 2.8013
F7 0.9859 0.9907 0.9987 Diffusion 1.9407
*Release rate constant of the diffusion mechanism.

gel formulations were found to have the same rank order in

Table 7. Percentage Inhibition as a Criterion for the
their antifungal activities as in the in vitro release studies. Antifungal Activity of Chlorphenesin in Its Different
Thus, the greatest activity was observed with formula F6, Emulgel Formulations
where the percentage inhibition reached up to 25.3%, while
Formulation % Inhibition Formulation % Inhibition
the lowest activity was found with F3 and F4, where the per-
CHL powder* 8.4 F5 20.2
centage inhibition was ~9%.
F1 11.1 F6 25.3
F2 16.2 F7 13.4
Stability Studies F3 9.4 F8 19.3
All the prepared CHL emulgel formulations were found to be F4 9.1
stable upon storage for 3 months, where no change was *CHL indicates chlorphenesin
observed in their physical appearance, pH, rheological prop-
REFERENCES
erties, drug release, or antifungal activity.
1. Sweetman SC. Martindale: The Complete Drug Reference. 33rd ed.
London, UK: The Pharmaceutical Press; 2002:381.
CONCLUSION 2. The Pharmaceutical Codex. 11th ed. London, UK: The Pharmaceutical
Press; 1979:181.
From the above results we can conclude that CHL emulgel
3. Eccleston GM. Emulsions. In: Swarbrick J, Boylan JC, eds.
formulations prepared with either Carbopol 934 or HPMC
Encyclopedia of Pharmaceutical Technology. Vol 5. New York, NY:
showed acceptable physical properties, drug release, and Marcel Dekker Inc; 1992:137-188.
antifungal activity, which remained unchanged upon storage 4. Rieger MM. Emulsions. In: Lachman L, Lieberman HA, Kanig JL,
for 3 months. However, the HPMC-based emulgel with the eds. The Theory and Practice of Industrial Pharmacy. 3rd ed.
liquid paraffin in its low level and the emulsifying agent in Philadelphia, PA: Lea and Febiger; 1986:502-533.
its high level proved to be the formula of choice, since it 5. Klich CM. Jels and Jellies. In: Swarbrick J, Boylan JC, eds.
showed the highest drug release and antifungal activity. Encyclopedia of Pharmaceutical Technology. Vol 6. New York, NY:

6
 The AAPS Journal 2004; 6 (3) Article 26 ([Link]
Marcel Dekker Inc; 1992:415-439. 11. Clearly GW. Transdermal controlled release systems. In: Langer RS,
6. Abd El-Bary A, Shalaby S, Abd El-Aal S. Formulation and stability of Wise DS, eds. Medical Applications of Controlled Release. Vol 1. Boca
chloramphenicol gel and emulgel. Bull Fac Pharm. 2001;39:89-99. Raton, FL: CRC Press; 1984:204-251.
7. Zhang XL, Zhao R, Qian W. Preparation of an emulgel for treatment of 12. Lucero MJ, Vigo J, Leon MJ. A study of shear and compression
aphthous ulcer on the basis of carbomers. Chin Pharm J. 1995;30:417-418. deformations on hydrophilic gels of tretinoin. Int J Pharm.
1994;106:125-133.
8. Hamza YE, Molokhia AM, Soliman II, Ahmed FH, Soliman NA.
Formulation and evaluation of topical preparations containing phenol and 13. Abd El-Bary A, Tayel S, Amin SY, Osman A. Bioavailability of
local vesicants. Az J Pharm Sci. 2002;29:412-432. salbutamol sulphate from different suppository formulations. Egypt J
9. Mohamed MI, Mortada ND. Development of a thermoreversible gel Pharm Sci. 1992;33:1031-1043.
for controlled-release ocular delivery of diclofenac sodium. Az J Pharm 14. Bolton S. Pharmaceutical Statistics. 3rd ed. New York, NY: Marcel
Sci. 1999;24:133-139. Dekker Inc; 1997:326-354.
10. Hugo WB, Russell AD. Pharmaceutical Microbiology. Oxford, UK: 15. Higuchi WI. Analysis of data on the medicament release from oint-
Blackwell Scientific Publications; 1977:190. ments. J Pharm Sci. 1962;51:802-804.