Research J. Pharm. and Tech. 5 (1): Jan. 2012
Comparative evaluation of Zidovudine loaded hydrogels and emulgels
Sushil Raut*1, Vaibhav Uplanchiwar1, Santosh Bhadoria1, Avinash Gahane1, Sunil Kumar Jain1,
1Adina Institute of Pharmaceutical Sciences, Sagar, (M.P.)-470002. India
2N.E.T. Pharmacy College, Raichur, (K.A.) - 584103. India.
Corresponding author: email@example.com
Zidovudine (AZT) is the widely used anti-retroviral drug associated with serious gastric side effects upon oral delivery
also having short half life and poor partition coefficient. Upon oral administration it also undergoes first pass
metabolism. Transdermal delivery of AZT encounters all the problems associated with oral route. The present study
we developed hydrogels as well as emugels loaded with AZT and investigated the ability of hydrogels as well as
emulgels to deliver the AZT via transdermal route. All the gels were evaluated for their physical properties, drug
content, viscosity, pH, spreadability and in vitro drug release. In vitro release pattern for all the formulations were
found to be zero order diffusion controlled release. All the formulations were found to be compatible with skin and
stable as per ICH guidelines. Among all the formulations emulgels were found to be effective vehicles for delivery
AZT because of the effective partition in both oil and aqueous phases.
KEYWORDS: Transdermal route, hydrogels, emulgels, in vitro, zidovudine.
Zidovudine (AZT), the first anti-HIV compound approved
for clinical use, still widely used for the treatment of AIDS
and AIDS related complex, either alone or in combination
with other antiviral agents.1 However, the main limitation to
the therapeutic effectiveness of AZT is its dose dependant
hematological toxicity. This virustatic drug has a very short
half-life of 1h and undergoes considerable first-pass
metabolism thus necessitating frequent administration of
large doses (200mg for every 4h) to maintain therapeutic
drug levels thus side effects occurs frequently.2 After per
oral administration AZT is completely and rapidly absorbed
thus leading to very high initial plasma concentrations and
consequently high incidence of toxicity. As AZT undergoes
considerable first-pass metabolism, transdermal route is a
better alternative to per oral administration, which
additionally provides better patient compliance1. The
transdermal route has vied with oral treatment as the most
successful innovative research area in drug delivery. The
negatives of oral route can be overcome, and benefits of
intravenous drug infusion such as to by-pass hepatic “first-
pass” elimination to maintain constant prolong and
therapeutic effective drug level in the body can be closely
duplicated, without its potential hazards, by transdermal
drug administration through intact skin.3
Received on 15.10.2011 Modified on 30.10.2011
Accepted on 09.11.2011 © RJPT All right reserved
Research J. Pharm. and Tech. 5(1): Jan. 2012; Page 41-45
Since, AZT is relatively polar molecule with a log P-0.09,
its transdermal permeability is poor and below the level
necessary to achieve a therapeutic effect2.
Attempts have been made to circumvent the skin barrier by
several means such as hydrogels and emulgels are
promising vehicles for successful delivery of AZT via
transdermal route.4 Hydrogels are three-dimensional, cross-
linked networks of water-soluble polymers. Hydrogels can
be made from virtually any water-soluble polymer,
encompassing a wide range of chemical compositions and
bulk physical properties. The unique physical properties of
hydrogels have sparked particular interest in their use in
drug delivery applications. Their highly porous structure
can easily be tuned by controlling the density of cross-links
in the gel matrix and the affinity of the hydrogels for the
aqueous environment in which they are swollen. Their
porosity also permits loading of drugs into the gel matrix
and subsequent drug release at a rate dependent on the
diffusion coefficient of
macromolecule through the gel network.5 Emulgel is
emulsions, either of the oil?in?water or water in oil type,
which are gelled by mixing with a gelling agent. Emulgels
are stable and better vehicles for hydrophilic as well as
hydrophobic drugs. Oil-in-water emulsions are most useful
as drug delivery water washable bases.6
In the present study, attempts had been made to develop
hydrogels as well as emulgels to compare the in vitro
permeation performance of AZT.
the small molecule or
Research J. Pharm. and Tech. 5 (1): Jan. 2012
MATERIALS AND METHODS:
AZT gifted from Aurobindo Pharma, Hyderabad. Tween-20
and Span-20 was purchased from NR Chem. Pvt. Ltd,
Mumbai. Carbopol 940, methyl paraben, propyl paraben,
liquid paraffin and propylene glycol (PG) was supplied by
Loba chemie, Mumbai. Ethanol and Triethanolamine (TEA)
was obtained from SD Fine chemical Ltd., Mumbai. All
other chemicals and solvents were of analytical grade.
Preparation of AZT hydrogels:
Appropriate quantity of carbopol 940 was soaked in water
for a period of 2 hours. Carbopol was then neutralized with
TEA with stirring. Then specified amount of AZT was
dissolved in appropriate and preweighted amounts of
propylene glycol and ethanol. Solvent blend was transferred
to carbopol container and agitated for additional 20 min.
The dispersion was then allowed to hydrate and swell for 60
min and pH was adjusted between 6.8-7 with TEA. During
pH adjustment, the mixture was stirred gently with a spatula
until homogeneous gel was formed.7
Figure 1: In vitro release of AZT from hydrogels
Figure 2: In vitro release of AZT from emulgels.
Preparation of AZT emulgels:
AZT emulgel was prepared by dispersing Carbopol 940
in distilled water with constant stirring at a moderate
speed then the pH are adjusted to 6.8 to 7 using TEA. The
oil phase of the emulsion was prepared by dissolving Span
20 in light liquid paraffin while the aqueous phase was
prepared by dissolving Tween 20 in distilled water. Methyl
and Propyl paraben was dissolved in PG whereas AZT was
dissolved in ethanol and both solutions were mixed with the
aqueous phase. Both the oily and aqueous phases were
separately heated to 70° to 80°C; then the oily phase were
added to the aqueous phase with continuous stirring until
cooled to room temperature. The obtained emulsion was
mixed with the gel in 1:1 ratio with gentle stirring to obtain
Table 1: Formulation of AZT hydrogels and emulgels.
AZT 1 1
Carbopol 940 0.5 1
Liquid paraffin - -
Tween 20 - -
Span 20 - -
PG 5 5
Ethanol 2.5 2.5
Methyl paraben 0.03 0.03
Propyl paraben 0.01 0.01
Evaluation of AZT gels:
The prepared hydrogels as well as emulgels containing
AZT were inspected visually for their color, homogeneity,
consistency and phase separation.9
Determination of pH:
The pH of the formulated hydrogels as well as emulgels
was determined using pH meter (Model: 7007, Digisun
electronics, Hyderabad). The electrode was immersed in
NOs and readings were recorded on pH meter.10
Drug content analysis:
A specified quantity (1.0 g) of gel was extracted with 5 mL
of ethanol and then volume was made upto 50 mL with
water, the 5 ml of the above solution was further diluted to
50 ml with distilled water. The absorbance of the solution
was measured spectrophotometrically at 266.5 nm against
blank and drug content was calculated.11
Determination of viscosity:
Viscosity studies of formulated gels were carried out using
cone and plate programmable Brookfield Rheometer
(Model: DV-??? ULTRA, Brookfield Engineering Lab; Inc;
Middleboro. USA) fitted with spindle Cp-52 at 100 rpm and
at temperature 25 ?C.12
Spreadability of AZT gels was determined by a wooden
block and glass slide apparatus, which was provided by a
pulley at one end. A ground glass slide was fixed on the
block and an excess of formulated gel (about 2 gm) was
placed on it. The gel was then sandwiched by using another
glass slide having the dimensions as that of fixed ground
slide and provided with the hook. Weight of 1 kg was
placed on the top of the two slides for few minutes to
remove entrapped air and to form a uniform gel film
between the slides. The excess of the gel was scrapped off
H1 H2 H3 E1 E2 E3
100 100 100
Research J. Pharm. and Tech. 5 (1): Jan. 2012
from the edges. Pulley was attached to the hook and 80 g
weight was incorporated to it. The time taken by the top
slide to travel a distance of 7.5 cm was noted.13
In vitro drug release studies:
AZT release rates from the gels were measured through
cellophane membrane using a modified Keishery chein cell.
Cellophane membrane allowed to equilibrating with the
diffusion medium for 15 minutes by immersing in diffusion
medium for 30 minutes. It was then placed on the support
screen of the diffusion cell assembly. All the joints were
properly sealed with adhesive tape to avoid the penetration
of diffusion medium. Saline phosphate buffer solution was
used as the receptor medium and 1 g of the test gel was
placed on the donor side. The receptor medium was kept at
32o C. At predetermined time intervals, 5 mL samples were
taken from the receptor compartment, for 12 h period and
replaced by the same medium to maintain a constant
volume. Absorbance of these solutions was measured at
266.5 nm using UV/VIS double beam spectrophotometer.
Cumulative percent release of AZT was calculated.14
Kinetics of drug release:
In order to investigate the mode of drug release from the
developed gels, the release rate were analysed according to
zero (equation ?) and first order (equation ??) kinetics as
well as diffusion controlled mechanism (equation ???-
Higuchi equation) using linear regression analysis.
?) Q = kot
Table 2: Evaluation parameters of AZT hydrogels and emulgels.
Formulation Code Colour
Table 3: Evaluation parameters and drug release kinetics of AZT hydrogels and emulgels.
code n=3 n=3
??) In (100-Q) = In Qo – k1t
???) Q = kH t1/2
In the above equations, Q is the percentage of drug released
at time t and ko, k1t and kH are coefficients of the equations.
The statistical analysis was performed by calculating the
correlation (r) existing between the in vitro release and the
proposed at different n-values.15
Skin compatibility studies:
Skin compatibility studies were carried out with the
permission of Institutional Animal Ethical Committee,
N.E.T. Pharmacy College Raichur, Karnataka, (IAEC No.
576/2002/bc/IAEC/CPCSEA). Albino rats (150-200 g) of
either sex were used for testing of skin irritation. The
animals were acclimatized under standard conditions with
free access to water Ad libitum. Hair was shaved from back
of rats and area of 4 cm2 was marked on both the sides, one
side served as control while the other side was test. AZT gel
was applied (500 mg/rat) twice a day for 7 days and the site
was observed for any sensitivity and the reaction if any.16
Accelerated stability studies:
All the formulations were subjected to a stability testing for
three months as per ICH norms at a temperature of 40º ± 2º.
All selected formulations were analyzed for the change in
viscosity, pH, drug content and phase separation by
procedure stated earlier.17
released in 12
h (Q) (±SD),
in 12 h
3.72 ± 0.01
3.42 ± 0.03
3.18 ± 0.04
3.94 ± 0.05
3.83 ± 0.03
3.65 ± 0.02
99.32 ± 0.22
98.52 ± 0.42
99.49 ± 0.34
99.55 ± 0.63
98.84 ± 0.24
98.92 ± 0.82
1854.2 ± 0.07
2932.6 ± 0.02
4382.2 ± 0.04
2988.7 ± 0.06
3319.3 ± 0.04
4738.8 ± 0.09
6.83 ± 0.11
6.91 ± 0.03
6.88 ± 0.13
6.84 ± 0.12
6.93 ± 0.18
6.96 ± 0.09
28.33 ± 0.09
33.48 ± 0.10
33.82 ± 0.74
37.69 ± 0.32
72.91 ± 0.11
67.05 ± 0.12
62.24 ± 0.23
77.20 ± 0.19
74.92 ± 0.13
71.47 ± 0.16
Table 4: Stability study data of AZT hydrogels and emulgels.
Code (±SD), n=3
H1 99.92 ± 0.53
H2 98.14 ± 0.84
H3 98.23 ± 0.12
E1 98.21 ± 0.32
E2 99.38 ± 0.24
E3 98.53 ± 0.45
Drug content (%) Viscosity (cps)
1834.4 ± 0.03
2183.3 ± 0.04
4324.3 ± 0.09
2734.3 ± 0.05
3264.2 ± 0.02
4738.4 ± 0.06
6.93 ± 0.13
6.97 ± 0.09
6.79 ± 0.05
6.73 ± 0.08
6.87 ± 0.13
6.82 ± 0.07
24.24 ± 0.43
29.84 ± 0.19
30.74 ± 0.46
34.84 ± 0.64
Research J. Pharm. and Tech. 5 (1): Jan. 2012
Figure 3: Comparative in vitro drug release between H1 and E1
AZT transdermal gels were formulated in order to bypass
the side effects associated with oral therapy. Hydrogels
(H1, H2 and H3) were formulated by using Carbopol 940 in
varying concentrations (0.5, 1 and 1.5 g) to provide the
adequate consistency and elegancy also it is free from the
toxicological effects on skin. In order to solublize the drug
in the formulation, PG was used as a solvent as well as
humectants to avoid the drying of gels.
Ethanol enhances the drug solubility in water because it acts
as a co-solvent. Excess amount of ethanol reduces the
viscosity of the formulated gels, this may be probably due
to break down of cross linking between the polymer hence
its concentration is optimum in the preparations i.e.
2.5%w/w. One more advantage of using ethanol is that it
enhances the drug permeation through the skin.
In another batch of formulation emulgels were developed
(E1, E2 and E3). Light liquid paraffin containing Span 20
acts as oil phase and water containing Tween 20 constitutes
aqueous phase. Along with the oil as well as water phases;
PG and ethanol also included in the formulation to enhance
solubility and permeability of the drug. Methyl and propyl
paraben are well known preservatives used to avoid the
microbial growth in both hydrogels as well as emulgels.
Formulated gels were tested for physical appearance,
homogeneity and consistency. All the hydrogels were found
to be transparent and homogenous with excellent
consistency where as emulgels were found to be opaque,
homogenous with good consistency and no phase separation
were observed. (Table 2) Drug content uniformity is the
indicative of uniform dispersion of drug throughout the
gels. The drug content of the formulated hydrogels and
emulgels were found in between 98.52 ± 0.42 to 99.55 ±
0.63% (Table 3).
A flow characteristic of the topical gels depends upon
viscosity of formulation. Since viscosity is inversely
proportional to the in vitro drug release hence a change in
viscosity reduces effectiveness of the product. Viscosity of
the hydrogel formulations depends upon the concentration
of Carbopol 940, it was found that gels H1, H2 and H3
having viscosities 1854.2 ± 0.07, 2932.6 ± 0.02 and 4382.2
± 0.04 cps in the concentration of 0.5, 1 and 1.5 g
respectively, whereas emulgels E1, E2 and E3 bear
viscosities as 2988.7 ± 0.06, 3319.3 ± 0.04 and 4738.8 ±
0.09 cps respectively. In the emulgels the gelling agent
concentration was kept constant (1%w/w) and the increased
viscosities from E1 to E2 may be due to increased
concentration of emulsifying agents (Span 20 : Tween 20).
The pH of the formulated gels not only influences the
solubility of drug in the formulation, but may also affect the
skin compatibility. Stability of the gels may affect, if the pH
changes throughout the shelf life. Hence, pH of the gels
must be even and in accordance with skin pH (5.4 to 6.9).
All the formulated gels have pH in the range of 6.83 ± 0.11
to 6.96 ± 0.09. (Table 3)
In order to give uniform applicability on the skin,
Spreadability of the gel is the essential consideration which
depends upon viscosity of the gels and these were in the
range of 28.33 ± 0.09 to 38.64 ± 0.21gcm/sec for all the
formulations. The in vitro drug release studies helpful to
optimize the gel formulations. Drug release studies were
carried out for 12 h from both hydrogels as well as
emulgels. It was observed that in vitro drug release from
hydrogels is inversely depends upon the Carbopol 940
concentration, as polymer concentration increases viscosity
of the gels increases and thus release rate decreases from
H1 to H3. (Table 3 and Figure 1)
In case of emulgels higher release rate was found in case of
formulation E1 and it decreases further with formulation E2
and E3. (Table 3 and Figure 2) It may be due to higher
viscosities of E2 and E3 which is the result of increased
concentrations of emulsifying agents (Span 20: Tween 20).
Comparison between hydrogels and emulgels with respect
to in vitro drug release profile revealed that emulgels are
capable to deliver AZT with higher release rates; it may be
due to partition of the drug in both oil as well as aqueous
phases. Figure 3 depicts that E1 is the better formulation
than H1 and among all the other formulations with respect
to all the properties.
Kinetics of drug release from the gels was studied by using
various mathematical models like first order, zero order and
Higuchi. (Table 3) The study revealed that all the gels
followed the zero order kinetics as their R2 values ranges
between 0.9789 to 0.9983 and the mechanism of the drug
release was found to be diffusion controlled (Higuchi data),
which is the rate limiting step in the drug permeation.
All the gels are composed of pharmaceutically approved
(non-immunogenic and biocompatible) excipients in desired
amounts. But still then there may be chances of some
allergic manifestations after applying on skin. Hence, the
Research J. Pharm. and Tech. 5 (1): Jan. 2012 Download full-text
skin compatibility study was carried out by using albino
rats. It was observed that all the gels showed some
behavioral changes in rats after first application, it may be
due to the cooling effect by the ethanol. But on further
application they showed the tolerability to that action. No
allergic manifestation was observed during study (Table 2).
With the purpose to deliver safe and effective formulation
throughout its shelf life to the patient it is very essential to
study the stability. When all the formulation were exposed
to exaggerated temperature condition (40º ± 2º), no changes
were found in their physical stability. Emulgels are the o/w
emulsions may undergo phase separation at higher
temperature. But the developed emulgels were found to be
stable without phase separation throughout the study period.
Also no significant changes were found in drug content,
viscosity, pH and spreadability of all the formulations.
The study concludes that transdermal delivery of AZT is
one of the better alternatives over the oral route which is
associated with serious side effects and emulgels are the
effective transdermal vehicles with attractive properties.
Panchagnula R and Narishetty S. Transdermal delivery of
Zidovudine: Effect of terpenes and their mechanism of action.
Journal of Control Release. 2004; 95: 367-79.
Panchagnula R and Narishetty S. Transdermal delivery of
Zidovudine: Effect of vehicles on permeation across rat skin and
their mechanism of action.
Pharmaceutics. 2003; (18): 71-79.
Soni M, Kumar S and Gupta GD. Transdermal Drug Delivery: A
Novel Approach to Skin Permeation. Journal of Pharmacy
Research. 2009, 2(8), 1184-1190
Kulkarni PK and Karatgi P. Emulsion- gels as topical drug
delivery vehicles- A Review. Indian Journal of Pharmaceutical
Education. 2002; 36(3): 119-23.
Kohane DS and Hoare TR. Hydrogels in drug delivery: Progress
and challenges. Polymer. 2008; 49: 1993-2007.
Khambete H et al. Gellified emulsion for sustain delivery of
itraconazole for topical fungal diseases. International journal of
Pharmacy and Pharmaceutical Sciences. 2010; 2(1): 104-112.
Japan Patel, et al. Formulation And Evaluation of Topical
Aceclofenac Gel Using Different Gelling Agent, International
Journal of drug development and research.2011; 3(1): 156-164.
Jain A, et al. Development and characterization of ketoconazole
emulgel for topical drug delivery. Der Pharmacia Sinica. 2010,
Mohamed MI. Optimization of Chlorphenesin emulgels
Formulation. American Association of Pharmaceutical Sciences.
2004; 6 (3): 1-7.
10) Raut SY, et al. Development and evaluation of non-ionic
surfactant based organogels for transdermal delivery of
Zidovudine. International Journal of Comprehensive Pharmacy.
2010, 3(7): 1-7.
11) Panigrahi L, et al. Effect of permeation enhancers on the release
and permeation kinetics of linkomycin hydrochloride gel
formulations through mouse
Pharmaceutical Sciences. 2006, 68 (2): 205-211.
12) Shishu and Aggarwal N. Preparation of hydrogels of griseofulvin
for dermal application. International Journal of Pharmaceutics.
326 (2006) 20–24.
International Journal of
skin. Indian Journal of
13) Kumar L and Verma R. In vitro evaluation of topical gel prepared
using natural polymer. International Journal of Drug Delivery.
2010; 2: 58-63.
14) Jani R et al. Preparation and Evaluation of Topical Gel of
Valdecoxib. International Journal of Pharmaceutical Sciences and
Drug Research. 2010; 2(1): 51-54.
15) Higuchi WI. Analysis of data on the medicament release from
ointments. Journal of Pharmaceutical sciences.1962; 51:802-04.
16) Kumar R, Patil MB and Patil SR. Evaluation of Anacardium
occidentale gum as gelling agent in Aceclofenac Gel.
International Journal of Pharmaceutical Technology and
Research. 2009; 1(3): 695-704.
17) Shivhare UD, et al. Formulation development and evaluation of
Diclofenac Sodium Gel using water soluble polyacrylamide
polymer. Digest Journal of Nanomaterials and Biostructures.
2009; 4 (2): 285-290.