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Development and optimization of novel diclofenac emulgel for topical drug

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Available online at www.pharmacie-globale.info ISSN 0976-8157

Research Article
PHARMACIE GLOBALE
INTERNATIONAL JOURNAL OF COMPREHENSIVE PHARMACY

DEVELOPMENT AND OPTIMIZATION OF NOVEL DICLOFENAC EMULGEL

FOR TOPICAL DRUG DELIVERY
P Vijaya Bhanu*1, V Shanmugam1 and P K Lakshmi2
1Department of Pharmaceutics, Sri Padmavathi School of Pharmacy, Tiruchanoor, Tirupathi, Andhra Pradesh, India.
2Department of Pharmaceutics, G Pulla Reddy College of Pharmacy, Medhipatnam, Hyderabad, Andhra Pradesh, India.
Received: 30 June 2011; Revised: 23 August 2011; Accepted: 29 August 2011; Available online: 5 September 2011

ABSTRACT
Diclofenac diethylamine is a Non-Steroidal Anti-Inflammatory drug, used in the treatment of inflammation and
degenerative disorder of the musculoskeletal system. The conventional diclofenac emulgel formulation contains
isopropyl alcohol to increase solubility of diclofenac diethylamine, it is highly flammable may cause eye and
cutaneous irritation. Prolonged skin contact with isopropyl alcohol may cause eczema and sensitivity. The working
hypothesis of this study was that to develop diclofenac emulgel without isopropyl alcohol and match the in vitro
and ex vivo permeability of optimized formulation with the conventional formulation. Formulation with Dispersion
of drug also available in market, it is also formulated and compared with marketed formulation.
Keywords: Diclofenac diethylamine, Emulgel, cetomacrogol, In-vitro and Ex-vivo Permeability study.

INTRODUCTION
Diclofenac is a well-established NSAID agent used for a
variety of painful and inflammatory conditions.1 It is
available as topical dosage form like gel, emulgel, lotion,
cream, and ointment and also available as of oral and
parentral dosage form. It should be used in long term for
musculo skeletal disorders like rheumatoid arthritis,
juvenile rheumatoid arthritis, osteoarthritis, ankylosing
spondylitis , but it produces GIT ulceration, liver and
kidney trouble especially in case of oral administration.2 In
view, of adverse drug reaction associated with oral
formulations, diclofenac is increasingly administered by
topical route.
Among various salts diclofenac diethylamine is widely
used for topical application due to its high lipophilic
nature.3 The conventional diclofenac emulgel formulation
contains isopropyl alcohol to increase solubility of
diclofenac diethylamine, it is highly flammable may cause
eye and cutaneous irritation. Prolonged skin contact with
isopropyl alcohol may cause eczema and sensitivity. A
further limitation is realized in fast termination of action
for gel preparations since the drug precipitates from
solution subsequent to water absorption from the body
tissue.4
Both oil-in-water and water-in-oil emulsions are
extensively used for their therapeutic properties and as
vehicles to deliver various drugs to the skin. Emulsions
possess a certain degree of elegance and are easily washed
off whenever desired. They also have a high ability to
penetrate the skin.5 In addition; the formulator can control
the viscosity, appearance, and degree of greasiness of
cosmetic or dermatological emulsions.
*Corresponding Author:
P Vijaya Bhanu
Department of Pharmaceutics, Sri Padmavathi School of Pharmacy,
Tiruchanoor, Tirupathi -517503. Andhra Pradesh, India.
Contact no:- +91-9052155880; Email: kvnshareddy@gmail.com
Oil-in-water emulsions are most useful as water washable
drug bases and for general cosmetic purposes, while
water-in-oil emulsions are employed more widely for the
treatment of dry skin and emollient applications.6
Gels for dermatological use have several favorable
properties such as being thixotropic, greaseless, easily
spreadable, easily removable, emollient, nonstaining,
compatible with several excipients, and water-soluble or
miscible.7
Emulgels are emulsions, either of the oil-in-water or water
in-oil type, which are gelled by mixing with a gelling
agent.8 They have a high patient acceptability since they
possess the previously mentioned advantages of both
emulsions and gels.9,10 Therefore, they have been recently
used as vehicles to deliver various drugs to the skin. They
are also called as creamed gel, quassi emulsion, gelled
emulsion.11-15
The main aim of the present work is to formulate the
diclofenac diethylamine emulgel 1.16%w/w without
isopropyl alcohol and to optimize the formulation by
performing in-vitro and ex-vivo diffusion studies.
MATERIALS AND METHODS
Gel materials
Diclofenac diethylamine and Crodamol GTCC were
procured as a gift sample from fourts India Pvt
Ltd,Chennai. Carbopol-934 and diethyl amine were
obtained from Balaj Amine Ltd, Maharastra. Propylene
glycol and liquid paraffin from Manali petrochem Ltd.
Cetomacrogal 1000 and Isopropyl alcohol collected from
Silvo Liacol and Shell. All the chemicals used in the study
were of pharmacopoeia quality (IP).
Method of preparation
Aqueous phase: Methyl paraben was dissolved in hot
water and transferred to planetary mixer. To this finely

1 Pharmacie Globale© (IJCP), Vol. 02, Issue 09

 Bhanu P V et al. / Pharmacie Globale (IJCP) 2011, 9 (10)

sieved carbomer 934 was dispersed by continuous stirring Drug solution preparation: Exact quantity of Diclofenac
at constant speed. Once the uniform dispersion attained diethylamine was accurately weighed and dissolved in
without lumps and bubbles, it is heated upto 75°C. propylene glycol. Isopropyl alcohol if mentioned in
Oil phase: Separately, required quantity of crodamol composition was added to the above mixture and stirred
GTCC, cetomacrogol 1000 and liquid paraffin were heated well. Diethyl amine as a neutralizing agent was mixed with
to 75°C and this was added slowly to above aqueous phase small quantity of water and added to the preformed
with continuous stirring until a fine emulsion forms. emulsion to get gelled emulsion (emulgel). (Table 1)
Table 1. Quantitative Composition of Diclofenac Sodium Emulgel Formulations (% wt/wt)
Ingredients (%) DFG 01 DFG 02 DFG 03 DFG 04 DFG 05 DFG 06 DFG 07 DFG 08 DFG 09 DFG 10 DFG 11 #DFG 12
Diclofenac diethylamine 1.16 1.16 1.16 1.16 1.16 1.16 1.16 1.16 1.16 1.16 1.16 1.16
Carbomer 934p 1 1.2 1.4 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2
Diethylamine 7.4 7.4 7.4 7.4 7.4 7.4 7.4 7.4 7.4 7.4 7.4 7.4
Propylene glycol 10 10 10 10 15 20 10 10 10 10 10 5
Crodamol GTCC 3 3 3 3 3 3 3 3 3 2.5 2.5 2.5
Liquid paraffin 2 2 2 2 2 2 2 2 2 2 2 2
Methyl paraben 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2
Cetomacrogol 1000 4 4 4 4 4 4 2.5 4 6 2.5 2.5 2.5
Isopropyl alcohol * * * * * * * * * 10 20 *
Purified water to produce 100 100 100 100 100 100 100 100 100 100 100 100
Where, # denotes that drug is in dispersed form; *Denotes that Isopropyl alcohol is not added
Physicochemical Evaluation Extrudability: The gels were filled into collapsible tubes
Homogenicity16: The formulations were tested for their after formulating them. The extrudability of the
homogeneity by visual appearance after the emulgel was formulation has been checked and the results were
applied as a thin layer on the slide. The results are tabulated Table 2.
tabulated in Table 2. Rheological studies17: The viscosity of the different
pH measurements: The pH measurements were done by emulgel formulations was determined at 25°C using a
using a digital type of pH meter by dipping the glass Brookfield viscometer with spindle no 96 at 1.5 rpm
electrode into the emulgel. The measured values are (Brookfield Engineering Laboratories, model HADV-II,
presented on the Table 2. Middleboro, MA). Results were shown in Table 2.
Table 2. Physicochemical properties of formulations
Formulation Code Extrudability Spreadability pH Homogenicity Viscosity (cps)
DFG 01 ** 22.89 6.53 ** 287500
DFG 02 ** 13.54 6.52 ** 395000
DFG 03 ** 10.03 6.65 ** 430000
DFG 04 ** 15.19 6.66 ** 386200
DFG 05 ** 19.62 6.72 ** 298600
DFG 06 ** 26.40 6.86 ** 230000
DFG 07 ** 10.17 6.52 ** 401200
DFG 08 ** 16.61 6.86 ** 365800
DFG 09 ** 27.32 6.79 ** 456000
DFG 10 ** 10.03 6.53 ** 492500
DFG 11 ** 10.51 6.62 ** 323600
DFG 12 ** 22.89 6.71 ** 421500
Marketed Sample ** 13.84 6.56 ** 354000
Where ** denotes good.
Spreadability18: One of the criteria for a gel to meet the Drug content analysis19
ideal qualities is that it should possess good spreadability. Assay of diclofenac diethyl amine was done with the help
Spreadability is a term expressed to denote the extent of of HPLC.
area to which the cell readily spreads on application to Sample solution: A weighed quantity of the emulgel
skin or the affected area. The therapeutic efficiency of the containing 50mg of Diclofenac Diethylamine is shaken
formation also depends on its spreadability values. Hence with 50 ml of acetone for 10 minutes, filtered and
determination of spreadability is important in evaluating evaporated to dryness under reduced pressure. Residue
gel characteristics. Spreadability is measured as: was dissolve in 100 ml of a mixture of 40 volumes of
water and 60 volumes of methanol, 1 volume of this
The spreadability of each sample was evaluated in solution was diluted to 10 volumes with the mobile phase
triplicate by mimicking the extensometer set up, which and filter through a glass fibre filter (Whatman GF/C is
consists of two glasses. The lower plate holds the sample, suitable).
while the upper plate, which weighs 32 gm, exerts forces Standard Solution: Contained 0.005% w/v of diclofenac
to the sample in the lower plate. 0.25 gm of paste was sodium BPCRS in methanol. The chromatographic
placed on the lower plate and the upper plate was placed procedure carried out using (a) a stainless steel column
on the top of the sample. Force was generated by adding (25 cm × 4.6 mm) packed with end-capped octylsilyl silica
known weight (50 gm) on the upper plate. Each sample gel for chromatography (5 µm) (end-capped Zorbax C8 is
was tested at least three times at constant temperature suitable), (b) as the mobile phase at a flow rate of 1 ml per
and exerted weight and the mean values of spread surface minute a mixture of 34 volumes of a mixture of equal
area on the lower plate were calculated and shown in volumes of a 0.1% w/v solution of orthophosphoric acid
Table 2. and a 0.16% w/v solution of sodium dihydrogen
2 Pharmacie Globale© (IJCP), Vol. 02, Issue 09
 Bhanu P V et al. / Pharmacie Globale (IJCP) 2011, 9 (10)
orthophosphate adjusted to pH 2.5 and 66 volumes of
methanol and (c) a detection wavelength of 254 nm.
The percentage content of C18H22Cl2N2O2 in the gel using
the declared content of C14H10Cl2NNaO2 in diclofenac
sodium BPCRS and taking each mg of C14H10Cl2NNaO2 to be
equivalent to 1.1609 mg of C18H22Cl2N2O2 was calculated.
The average drug content was calculated using the
following formula and noted in Table 3.
Table 3. HPLC results of selected formulation and
calculated Drug content
Formulation Peak area Drug Content (% w/w)
DFG_01 1017.00 101.41
DFG_02 982.65 98.57
DFG_03 1209.60 103.27
Marketed Product 996.79 99.71
Percentage of assay:
In-vitro drug release studies20
Release of diclofenac diethylamine from optimized
formulation and the marketed formulation as standard
was studied employing the permeation apparatus
designed as described. A glass cylinder with both ends
open, 10 cms height, 3.7 cms outer diameter and 3.1 cms
inner diameter was used as permeation cell. A cellophane
membrane, (soaked in glycerin for 2 hours before use)
was fixed to one end of the cylinder with the aid of an
adhesive to result as a permeation cell. 0.5 gms of
medicated emulgel was taken in the cell (donor
compartment) and cell was immersed in a beaker
containing 100 ml of 7.4 pH phosphate buffer as receptor
compartment. The entire surface of the cell was in contact
with the receptor compartment which was agitated using
magnetic stirrer and a temperature of 37±1°C was
maintained. Samples (5 ml) of the receptor compartment
were taken at 30 min interval of time over a period 8
hours with same amount replaced. The sample was
analyzed for diclofenac diethylamine at 254 nm against
blank using UV Spectroscopy. Amount of diclofenac
diethylamine released at various time intervals was
calculated with the help of calibration curve with
phosphate buffer pH 7.4 and plotted against time.
Ex-vivo permeation studies21
Male rats weighing 105-120 gm free from any visible sign
of disease were selected. Using a depilatory preparation
hair was removed from the skin and the cleared area was
washed thoroughly with distilled water. Abdominal skin of
full thickness was excised from the rat. This was mounted
on the donor compartment. The emulgel was placed over
it and the permeation study was carried out in the similar
manner as that with artificial membrane.
RESULTS AND DISCUSSION
Initially DFG 01, 02, 03 were prepared to optimize the
concentration of polymer carbomer 934 P, the
spreadability and extrudability of DFG 01 was high, its
consistency is very thin and the viscosity was low. In DFG
03, the spreadability was low and the viscosity was very
high. It was found the formulation with 1.2 % carbomer
934 (DFG 02) has good spreadability, extrudability and
viscosity.
Propylene glycol concentration was optimized with the
formulation DFG 04, DFG 05 and DFG 06. In this DFG 05,
during drug solution preparation, the drug was not
dissolved properly and it was slightly heated to dissolve
the drug. When DFG 06 was applied on the skin, the drying
3 Pharmacie Globale© (IJCP), Vol. 02, Issue 09
time was high and so it looks oilier. DFG 04 with 10 %
propylene glycol concentration was good.
To optimize the cetomacrogol 1000 concentration,
formulations DFG 07, DFG 08 and DFG 09 were prepared
with 2.5%, 4% and 6%. During formulation, DFG 08
composition produced better emulsion compare to other
two formulations. Isopropyl alcohol concentration was
finalized with the formulation DFG 10, DFG11. In this DFG
11 with 20 % was found well, there were no drug particles
when viewed under microscope, it gives the evidence that
the drug was dissolved properly. To compare for the
permeability of dispersed and dissolved drug,
formulations were viewed under the microscope. The
diclofenac particles were clearly seen. Based on the
viscosity, spreadability, homogenicity and extrudability
DFG 02, DFG 11and DFG 12 was chosen for further studies.
The pH of all formulation is kept between pH 6.2 to 6.8.
The pH is a main parameter here since above pH 7 the
formulation colour changes to pink colour and below pH 5
the drug solubility was less and also to avoid skin
irritation.
Drug Content analysis
Drug content for each formulation was calculated, it shows
98% to 105% of the same. It complies with the BP
standard and indicates that the drug is distributed almost
uniformly throughout the formulation and there was no
loss of drug in formulation.
In-vitro result shows that DFG 12 release was less when
compared to other formulations, this may be because the
drug first dissolves in the donor compartment and then
permeate through the artificial membrane to acceptor
compartment. (Figure 1)
Figure 1. Comparative in-vitro drug release graph
The diffusion study result for formulation DFG 02
(90.72%), DFG 11(93.10 %) was significant with that of
marketed formulation.
Ex-vivo study was done with formulation DFG 02, DFG11
and DFG12, its shows ex-vivo release of all formulation
were less than in-vitro release. This may be due to the fat
content and thickness of Rat skin. Release of DFG12 was
very less than other two formulations. The difference in
release of drug of DFG 02, DFG11 was very less.
Figure 2. Comparative ex-vivo drug release graph
 Bhanu P V et al. / Pharmacie Globale (IJCP) 2011, 9 (10)
CONCLUSION
The present study concludes that the formulation
developed shows its physiochemical properties like
spreadability, homogenicity, viscosity, and consistency are
good. All the results were comparable with the marketed
sample and the drug content also within BP limit.
Permeability study shows that DFG 11 and DFG 02 have
comparable drug release with that of marketed product.
Thus the study reveals that this diclofenac diethylamine
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The project was done in K M College of Pharmacy,
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