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Formulation and in vitro evaluation of Cream containing Diclofenac Sodium

and Curcuma Longa for the management of Rheumatoid Arthritis

Article · July 2014

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International Journal of Pharma Sciences
Vol. 4, No. 4 (2014): 654-660
Research Article
Open Access
ISSN: 2320-6810

Formulation and in vitro evaluation of Cream

containing Diclofenac Sodium and Curcuma Longa for
the management of Rheumatoid Arthritis
Muhammad Razi Ullah Khan1, 2*, Shahaid Masood Raza1 and Musaddiq Hussain1
1
School of Pharmacy, The University of Faisalabad, Faisalabad, Pakistan
2
Faculty of Pharmacy, University of Sargodha, Sargodha, Pakistan

* Corresponding author: Muhammad Razi Ullah Khan; e-mail: razi_pharmacist@yahoo.com

Received: 23 June 2014 Accepted: 08 July 2014 Online: 21 July 2014

ABSTRACT
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently prescribed drug groups. These
drugs are used dermal or systemically in treatment of various rheumatic diseases, including Rheumatoid arthritis
(RA), as well as for Osteoarthritis, low back pain and some joint diseases. Diclofenac sodium is a well tolerated
NSAID because of its limited numbers of adverse effects and topical formulation has excellent permeation and
absorption into the skin and is frequently prescribed for the long term treatment of Rheumatoid arthritis,
Osteoarthritis and Ankylosing spondylitis. The present investigation was to develop novel cream formulation
containing Diclofenac sodium in combination with most effective and potent natural anti-inflammatory agent
curcuma longa, which is reported to possess strong anti-inflammatory effects in Rheumatoid arthritis and
Osteoarthritis, according to the study by University of Arizona researchers. Diclofenac sodium in combination with
Curcuma longa is a good rational, where curcuma longa produces synergistic anti-inflammatory effects with
Diclofenac sodium. Formulation containing fixed concentrations (1%) of Diclofenac sodium with curcuma longa
was prepared. To access the efficacy of formulation different in-vitro tests including stability studies, tube extrude
ability, spread ability, pH, skin irritation test, viscosity and rheological properties, drug diffusion study and anti-
inflammatory studies were carried out. The results obtained were encouraging and formulation containing
Diclofenac sodium (1%) with curcuma longa was found better than alone Diclofenac sodium cream formulation.

Keywords: Diclofenac sodium, Curcuma longa, Rheumatoid arthritis, Cream.

INTRODUCTION population is affected [6]. Diclofenac Sodium a Non

In the last few decades there has been an exponential
growth in the field of herbal medicine. It is getting
popularized in developing and developed countries
owing to its natural origin and lesser side effects
[1].The scientific evidence has brought about the
possibility of utilization of herbal plant in the treatment
of inflammatory diseases and the development of anti-
inflammatory products [2]. Inflammation is a tissue
reaction by the body to injury and involves a complex
array of enzyme activation, mediator release,
extravasations of fluid, cell migration, tissue
breakdown and repair [3]. Rheumatoid arthritis
represents the commonest form of chronic
inflammatory joint disease [4]. Arthritis is one of the
most distressing and disabling syndromes encountered
in medical practice [5]. An estimated 1-2% of adult
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Steroidal Anti-inflammatory agent is frequently
prescribed for the long term treatment of Rheumatoid
Arthritis, Osteoarthritis and Ankylosing Spondylitis [7].
The drug undergoes substantial first pass effect and
only 50% of drug is available systemically [8]. Further,
the drug is known to induce ulceration and bleeding of
the intestinal wall. To avoid the adverse effect,
alternate routes of administration have been tried by
investigators [9]. Delivery of Diclofenac Sodium via skin
offers the potential advantage of by passing
gastrointestinal first pass metabolism associated with
oral administration [10]. Turmeric (the Common name
for Curcuma longa) is a perennial member of the
Zingiberaceae family, derived from the rhizomes of the
plant and has a long history of use in Ayurvedic
medicine as a treatment for inflammatory conditions
[11]. The major pigment compound of Curcuma longa is
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Curcumin which has been shown to have including
cytokines (TNF alpha and IL-1 beta) [12]. The present
research has been undertaken with the aim to develop
a topical Diclofenac Sodium cream formulation along
with the Curcuma longa, which would attenuate the
gastrointestinal related toxicities associated with oral
dosage forms. Diclofenac Sodium having molecular
weight of 296.1 and melting point of 157°C can be
considered ideal to permeate through the skin.
various solvents ranging from non polar to polar. 1 lit
of solvent was added and extracted according to their
boiling point for seven hours. The solvents used were
chloroform (B.P. =61˚C), ethyl acetate (B.P. =77˚C),
methanol (B.P. =65˚C) and acetone (B.P. =56.53˚C).
After completion of extraction the dark brown extract
was then cooled, concentrated using rotary evaporator
get a crude dried extract which was black orange in
color.

MATERIALS AND METHODS Formulation of Diclofenac Sodium Cream

Chemicals: containing Curcuma longa:
Diclofenac Sodium was received as a gift from Sami 1% by weight of Diclofenac Sodium cream containing
Pharmaceuticals Pakistan , Stearic Acid (BDH labs, curcuma longa was made according to the formulation
England), Stearyl Alcohol (BDH Labs, England), Bees given in Table I.
Wax (Kukdong oils and chemicals, Korea), Methyl
Parabens (BDH labs, England), Liquid Paraffin Table I: Formulation of Diclofenac Sodium cream containing
(Kukdong oil and chemicals, Korea), Polyoxyethylene Curcuma longa
(80) Sorbitan monooleate (Tween 80) (Merck, S. No. Ingredients Percentage Composition
1 Diclofenac Sodium 1.0
Germany), Potassium Hydroxide (Merck, Germany), , 2 Curcuma longa 3.0
Sorbitol liquid USP (Merck, Germany) and De-ionized 3 Liquid Paraffin 5.0
water (Medilines Diagnostic division) 4 Stearic Acid 0.30
5 Bees Wax 5.0
6 Stearyl Alcohol 10.0
Plant Material: 7 Tween-80 8.0
Plant material used for that study was collected from 8 Methyl Parabens 0.12
the surroundings of Kasur city of Pakistan in the month 9 Sorbitol Solution 6.0
of March and identified by Department of Botony, 10 Potassium Hydroxide 1.50
11 De-ionized Water 60.08
Faculty of Biological Sciences, University of Sargodha
Pakistan.
Preparation of cream:
Apparatus: Diclofenac Sodium cream with turmeric extract was
Beaker 50ml, 100ml (Pyrex, England), Pipette 10ml formulated by the method of Nazir et al [13]. The
(Preciclolor, Germany), Conical flask 50ml, 100ml aqueous and oil phases were taken into bakers and
(Pyrex, Germany), White colored jar, Amber colored heated to 75ºC over a water bath. The oil phase was
comprised of Diclofenac Sodium, Liquid Paraffin, Bees
glass jar, Aluminum foil and Aluminum collapsible tube.
Wax, Stearyl Alcohol, Tween-80 and Stearic Acid while
the aqueous phase was composed of Extract of
Instruments:
Spectrophotometer U.V1700 (Shimdazu, Japan), Curcuma longa, Methyl parabens, Sorbitol Solution and
Magnetic stirrer/ Hot plate (Made in Germany), Potassium Hydroxide. Drop wise addition of the
Weighing balance (Analytical grade), pH meter (Model aqueous phase to the oil phase was done with constant
No: 3510, England), Keshary-chien diffusion cell, stirring at 2000 rpm in a homogenizer for a period of
Homogenizer (Euro-Star, IKA D 230, Germany), 15 min. The homogenizer speed was then reduced to
Brookfield digital viscometer (model DV-II+, Brookfield 1000 rpm and homogenization was continued for
Engineering Laboratory, INC. USA), Refrigerator another 5 min. The speed was further reduced to 500
(Dawlance, Pakistan), Incubator (Sanyo MIR-162, rpm and the homogenization extended for 5 min.
Japan), Oven (Schutzartdin 40050 IP-20, Germany), Diclofenac cream containing the Curcuma longa extract
Soxhlet Apparatus. was formulated.

Animals:
Albino rats of either sex weighing between 200-250 g
were used for the present investigation. The rats were
housed at controlled temperature (25±2ºC) and 12hrs
dark-light cycle and provided basal diet in the form of
pellets, water and libitum.
Organoleptic Evaluation:
Changes in organoleptic properties of the cream were
evaluated by visual inspection and the properties
evaluated included the color of the creams, liquefaction
and phase separation. These were evaluated over a
period of 3 months at specific time intervals.

Preparation of Turmeric Extract: Physical Evaluation of Cream:

The rhizomes of curcuma longa (Turmeric) were
cleaned, washed with de-ionized water, sliced and
dried in the sun for one week. Dried rhizomes were cut
in small pieces and powered by electronic mill. 200 gm
of sample was taken into thimble and placed in a
Soxhlet apparatus. The apparatus was setup with
Physical evaluation including the determination of pH,
Spread ability, Tube extrudes ability and viscosity was
carried out on the cream at the time of preparation (at
zero time) and thereafter every month until 3 months
period.

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Determination of pH:
The pH measurement was carried out by using a
calibrated digital type pH meter by dipping the glass
electrode and the reference electrode completely into
the cream so as to cover the electrodes [14]. pH was
determined at the time of preparation and on monthly
basis for the 3 months period.
Determination of Spread ability:
Spread ability of cream was determined by the
apparatus which consists of a wooden block, which was
provided by a pulley at one end [15]. By this method
spread ability was measured on the basis of slip and
drag characteristics of cream. An excess of cream
(about 2g) under study was placed on this ground slide.
The cream was then sandwiched between this slide and
another glass slide having the dimension of fixed
ground slide and provided with the hook. 1 kg weighted
was placed on the top of the two slides for 5 minutes to
expel air and to provide a uniform film of the cream
between the slides. Excess of the cream was scrapped
off from the edges. The top plate was then subjected to
pull of 80 gm. With the help of string attached to the
hook and the time (in seconds) required by the top
slide to cover a distance of 7.5 cm be noted. A shorter
interval Indicate better spread ability. Spread ability
was calculated using the following formula:
S=M×L/T
Where,
S = Spread ability,
M = Weight in the pan (tied to the upper slide)
L = Length moved by the glass slide
T = Time (in sec.) taken to separate the slide
completely each other.
Determination of Tube Extrude ability:
Tube extrude ability was determined by filling the
cream in clean, lacquered aluminum collapsible tube
and pressed firmly at the crimped end. When the cap
was removed, cream extruded until pressure
dissipated. Weight in grams required to extrude 0.5 cm
ribbon of cream in 10 seconds was determined [16].
Determination of Viscosity:
Viscosity of cream was determined by Brookfield
viscometer. The viscosity measurements were done
using Brookfield DV-II + viscometer using LV-4 spindle.
The developed formulation was poured into the
adaptor of the viscometer and determined the viscosity
of the test sample as per standard operating procedure
of viscometer. The spindle was rotated at speeds of 0.5,
1, 5, 10 and 20 rpm. The reading near to 100% torque
was noted [17].
In Vitro Diffusion Studies:
The diffusion studies were performed using a Keshary-
chien diffusion cell. The cell was locally fabricated and
had a 25 ml receptor compartment. The dialysis
membrane was mounted between the donor and
receptor compartments. The cream formulation was
applied uniformly on the dialysis membrane and the
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compartments were clamped together. The receptor
compartment was filled with the phosphate buffer (pH
7.4) and the hydrodynamics in the receptor
compartment were maintained by stirring with a
magnetic bead. The study was carried out for 24 hrs
with the interval of 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 hrs.
1ml of samples was withdrawn from the receptor
compartment at pre-determined time intervals and an
equal volume of buffer was replaced. The samples were
analyzed after appropriate dilution for drug content
Spectrophotometrically at 280 nm [18].
Skin Irritation Study:
In skin irritation test 0.5 gm of the cream formulation
was used as the test substance was applied to an area
of approximately 6 cm2 of skin and covered with a
gauze patch. The patch was loosely held in contact with
the skin by means of a semi-occlusive dressing for the
duration of 1 hour and gauze was removed. At the end
of the exposure period, i.e., 1 hour, residual test
substance was removed, without altering the existing
response or integrity of the epidermis. Observations
have recorded after removal of the patch. The cream
was applied to the skin once a day for 7 days and
observed for any sensitivity and the reaction if any was
graded [19].
Stability Studies:
Stability studies on the cream formulation were
conducted over a period of 6 months at three different
conditions: (a) At 25 ± 1ºC (b) at 40 ± 1ºC (c) at 65 ±
1ºC. The cream was analyzed by UV- Visible
Spectrophotometer, immediately after preparation (at
zero time) and after every month until 6 months period
[20].
The active contents in cream formulation were
determined by measuring the absorbance of sample
solution on UV Spectrophotometer at 280nm
wavelength at above mentioned time intervals and by
calculating the remaining %age of active content by
following formula:
Remaining %age of active content in sample
solution = (Absorbance of Sample / Absorbance of
Standard) × (Conc. of Standard / Conc. of Sample) × %
age purity of Standard [21].
Determination of Drug contents by
Spectrophotometric Method:
Preparation of Standard Solution:
50 mg of Diclofenac sodium was carefully weighted on
analytical balance and dissolved in ethanol (96%) and
made the volume upto 100ml with ethanol. The
solution was then filtered and 1ml was taken from that
solution and made the volume of that solution up to
50ml with same solvent and it was taken to be the
standard solution in UV Visible spectrophotometer.
Preparation of Sample Solution:
5 g of the cream formulation was taken and dissolved in
ethanol (96%) and made the volume up to 100ml with
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the same solvent. The solution was then filtered and 1
ml was taken made up to 50 ml with ethanol. The
absorbance was measured at 280nm using ethanol as
blank solution.
RESULTS AND DISCUSSION
The purpose of the present investigation was to
develop a topical Diclofenac sodium cream formulation
along with a most effective and natural anti-
inflammatory agent, curcuma longa, that conveniently
deliver the drug to the localized area of the skin and is
used for the management of Rheumatoid arthritis and
does not produce any undesirable side effects.
Diclofenac sodium cream along with potent anti-
inflammatory agent Curcuma longa was prepared using
different concentration of excipients and active
ingredient. Accelerated stability study was done at 25 ±
1°C, 40 ± 1°C and 65 ± 1°C. Stability testing was done
for the period of 6 months (180 days). It is evident from
the results that cream formulation is best suitable at
(25 ± 1°C) as % age of drug remaining is not decreased
by more than 10% [22]. It is also evident from the
results of standard deviation at the end of 6 months
that at 25 ± 1°C standard deviation was least and it fell
into acceptable range, but at 40°C and 65°C the
standard deviation is bit higher and away from normal
and reasonable range. So it can be concluded, that at 25
± 1°C, the cream formulation fulfils the criteria required
for a pharmaceutical cream preparation to be
acceptable concerning accelerated stability studies.

Table II percentage remaining of drug content at zero time

Absorption of Absorption of Sample Percentage of active Mean Standard Deviation
Standard drug in the sample
0.625 0.623 99.28% 0.624 0.001414

Table III percentage remaining of drug content after 1 month

Absorption of Sample Percentage of active Mean Standard Deviation
drug in the sample
At 25 ± 1°C 0.617 98.32% 0.621 0.005656
At 40± 1°C 0.612 97.52% 0.618 0.009192
At 65 ± 1°C 0.610 97.20% 0.6175 0.01060

Table IV percentage remaining of drug content after 2 months

Absorption of Sample Percentage of active Mean Standard Deviation
drug in the sample
At 25 ± 1°C 0.604 96.25% 0.6145 0.014849
At 40± 1°C 0.597 95.13% 0.611 0.019798
At 65 ± 1°C 0.595 94.81% 0.61 0.021213

Table V percentage remaining of drug content after 3 months

Absorption of Sample Percentage of active Mean Standard Deviation
drug in the sample
At 25 ± 1°C 0.597 95.04% 0.611 0.019798
At 40± 1°C 0.585 93.22% 0.6105 0.028284
At 65 ± 1°C 0.581 92.58% 0.603 0.0311112

Table VI percentage remaining of drug content after 4 months

Absorption of Sample Percentage of active Mean Standard Deviation
drug in the sample
At 25 ± 1°C 0.590 94.92% 0.607 0.024748
At 40± 1°C 0.568 90.51% 0.596 0.040305
At 65 ± 1°C 0.563 89.71% 0.594 0.043840

Table VII percentage remaining of drug content after 5 months

Absorption of Sample Percentage of active Mean Standard Deviation
drug in the sample
At 25 ± 1°C 0.581 92.58% 0.603 0.031112
At 40± 1°C 0.547 87.16% 0.586 0.055154
At 65 ± 1°C 0.543 86.53% 0.584 0.057982

Table VIII percentage remaining of drug content after 6 months

Absorption of Sample Percentage of active Mean Standard Deviation
drug in the sample
At 25 ± 1°C 0.572 91.15% 0.598 0.037476
At 40± 1°C 0.531 84.62% 0.578 0.066468
At 65 ± 1°C 0.526 83.82% 0.575 0.070003

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 Muhammad Razi Ullah Khan et al. / Int J Pharma Sci. 2014, 4(4): 654-660

% age concentration of drug

Time in Months

Figure I. A graphical representation between percentage of drug concentration and time in months

The visual appearance of cream formulation was
checked at the time of preparation and at the end of
every month until 3 months period. The cream was
light yellowish in colour and had a cool and smooth
feeling on application and there was found no
significant difference in visual appearance at the end of
three months period from the time of preparation. pH
evaluation is also important to check the stability of
cream formulation. The pH of prepared cream with
extract was found to be around 6 which is suitable for
topical application because the pH of skin is between
4.5-6. The result of spread ability varies from 12.78 to
17.01g/sec whereas the extrude ability of cream
formulation from the collapsible tube varies from 180
to 190 g as shown in table IX. At 0.5 rpm to 20 rpm
viscosity was decreased from 6896 to 671 cps. So, if we
decrease the rate of shear it increases the viscosity of
cream. Viscosity of creams is inversely proportional to
rate of shear (rpm) and the results are showed in table
no. X.

Table IX Evaluation data of Diclofenac cream with herbal extract

Parameters evaluated Study Period
At Zero time 1 Month 2 Months 3 Months
Visual appearance Light Yellowish No change No change No change
pH 6.79 6.81 6.78 6.80
Spread ability (g/sec) 12.78 14.12 15 17.01
Tube extrude ability (g) 180 180 185 190

Table X Viscosity of cream formulation (cps) at different rpm

Speed in rpm At Zero time 1 Month 2 Months 3 Months
0.5 6710 6825 6883 6896
1.0 3147 3271 3291 3343
5.0 1614 1621 1591 1618
10 931 964 939 986
20 625 642 659 671

In Vitro Drug Diffusion study: releases 84.19% of drug over a period of 24 hours as
From the data we have found that the prepared topical shown in Table XI. From the In – vitro drug diffusion
Diclofenac cream formulation with herbal extract study we have concluded that the cream formulation

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 Muhammad Razi Ullah Khan et al. / Int J Pharma Sci. 2014, 4(4): 654-660

prepared, controls the release of drug for longer period Skin Irritation Test:
of time which will be helpful to avoid the more In skin irritation test, no signs of erythema and edema
fluctuation and also reduces the cost of therapy. were found after 7 days of cream application in rats
and are graded in table XII.

Table XI in Vitro Drug Diffusion Study over period of 24 Hours

Time (Hours) Percentage of drug release
0.0 0.0
0.5 7.78
1.0 15.77
2.0 23.57
4.0 34.98
6.0 43.03
8.0 51.17
10.0 66.82
12.0 74.45
24.0 84.19

Table XII Skin irritation study results over 7 days period

Treatment Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7

Rats A A A A A A A
A – No reaction, B – Slight patchy erythematic, C –Slight but confluent or moderate but patchy erythematic, D – Moderate erythematic, E – Severe
erythematic with or without edema.

CONCLUSION 7. M C Gohel, et al (2000). Application of simplex lattice design

The present cream formulation was developed by
taking into consideration that in cream formulations
there is present no direct contact of active drug with
stomach wall. This can be a reason to remove the
chances of gastric mucosal damage to a reasonable
level that is caused by the use of solid dosage forms of
NSAIDs. The cream formulation contains Diclofenac
Sodium along with extract of Curcuma longa , a spice
most often found in curry dishes may help prevent
Rheumatoid arthritis and Osteoporosis. Diclofenac
Sodium is an NSAID that is very effective to mimic the
pain and inflammation in arthritis patients and
Curcuma longa performs a synergistic anti-
inflammatory effect.
Acknowledgements
The authors are thankful to The University of Faisalabad,
Faisalabad, Pakistan for providing necessary laboratory
facilities to carryout work with great ease and precision and
also acknowledge with special thanks to Sami
Pharmaceuticals, Pakistan for providing the Diclofenac
sodium active material as a gift sample for present work.
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