Pharmaceutical Development and Technology, 2011; 16(5): 497–510

© 2011 Informa Healthcare USA, Inc.

ISSN 1083-7450 print/ISSN 1097-9867 online
DOI: 10.3109/10837450.2010.495394

RESEARCH ARTICLE

In vitro release, rheological, and stability studies of

mefenamic acid coprecipitates in topical formulations
Tarek A. Ahmed1, Hany M. Ibrahim1, Fathy Ibrahim1, Ahmed M. Samy1, Ehab Fetoh1, and
Mohammad T. H. Nutan2
1
Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt,
and 2Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University Health
Science Center, Kingsville, Texas, USA

Abstract
A suitable topical formulation of mefenamic acid was developed in order to eliminate the gastrointestinal
disorders associated with its oral administration. Drug coprecipitates prepared with different polymers
at various drug-to-polymer ratios improved drug solubility and dissolution compared to pure drug and
physical mixtures. PVP polymers (ratio 1:4) produced the best results. Aqueous ionic cream, ointments of
absorption and water soluble bases and gels of methylcellulose, carboxymethylcellulose sodium, HPMC,
Carbopol® 934 and 940, and Pluronic® F127 bases containing 1–10% drug as coprecipitates of PVP polymers
(1:4) were prepared. The highest drug release was achieved at 1% drug concentration from water soluble
base and methylcellulose among cream/ointment and gel bases, respectively. Gels, in general yielded better
release than creams/ointments. All tested medicated creams/ointments exhibited plastic flow while all gels
conformed to pseudoplasticity. Most of them showed thixotropy, a desired property of topical preparations.
Stability studies revealed that HPMC and methylcellulose had the smallest changes in drug content, viscosity,
and pH among the formulations. Considering drug release, rheological properties, and stability, methylcel-
lulose gel containing 1% drug as coprecipitates of PVP K90 was the best among the studied formulations,
was promising for improving bioavailability of mefenamic acid and can be used in future studies.
Keywords:  Mefenamic acid; topical; coprecipitates; PVP K90; gel; methylcellulose

Introduction strategies had been used to overcome the ­problems

Mefenamic acid (MA) is a non-steroidal anti-inflammatory
drug (NSAID), one of the most widely used groups of
therapeutic agents in clinical practice.[1] MA is available
worldwide in the form of tablets, capsules, and pediatric
suspensions. However, oral administration of MA creates
gastrointestinal disorders as side-effects.[2] MA is not avail-
able in the market as topical preparation and very limited
studies have been done so far to evaluate the viability of
its topical administration. Therefore, formulation factors
affecting the properties of topical preparations of MA have
been studied in this project.
MA has a number of undesirable physico-chemical
properties including its poor solubility in water.[3,4] Various
arising from its poor aqueous solubility and to attain
improved bioavailability. Among these strategies were the
use of penetration enhancers[5] and prodrug approach.[6]
However, none of these methods was completely satisfac-
tory. MA is a BCS Class II drug having the characteristics
of low solubility and high permeability.[7] Therefore,
solubility is the rate limiting factor for its bioavailability.
Hence, the approach was taken in this study to formulate
a good topical preparation of MA with improved solubil-
ity and better drug release from the dosage form.
Solid dispersion technique increases solubility,
dissolution, and absorption of poorly water soluble
drugs and can also be used to formulate sustained
release dosage forms and liquid drugs adsorbed on

Address for Correspondence:  Dr Mohammad T.H. Nutan, Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M
University Health Science Center, 1010 West Avenue B, MSC 131, Kingsville, TX 78363, USA. E-mail: mnutan@pharmacy.tamhsc.edu

(Received 29 May 2009; revised 03 May 2010; accepted 14 May 2010)

497
 498   T.A. Ahmed et al.
inert matrix in solid dosage forms.[8–10] Various methods
including melting (fusion), solvent (coevaporation),
and melting-solvent methods were used in preparing
solid dispersions. Solid dispersions prepared by solvent
(coevaporation) method are known as coprecipitates
or coevaporates.[11] Coprecipitates of mefenamic acid
were prepared in this study to improve drug solubility
and dissolution.
Ointments are greasy or non-greasy preparations
depending on the type of base used. They are intended
for external application to the skin or mucous mem-
branes for protective, therapeutic, or prophylactic
purposes. Creams are semisolid emulsions and are
usually applied topically as medicated or unmedicated
products. Oil-in-water type creams are water washable
and are more cosmetically and aesthetically acceptable
than water-in-oil type creams. Gels, on the other hand
are semisolid preparations containing large proportions
of water. They are used pharmaceutically as lubricants
and also as carriers for many drugs for their local effect
and percutaneous absorption.[12] Gels are particularly
suitable for water soluble medicaments and are less
satisfactory for insoluble substances which are often
difficult to be incorporated uniformly.
The objective of the present study was to develop a
good topical formulation of mefenamic acid through a
series of studies including the preparation of MA copre-
cipitates using several polymers and incorporating
them in an aqueous ionic cream and several ointment
and gel bases. This formulation might give a lead to an
alternative route of administration of the drug in order
to avoid gastrointestinal disorders of MA through oral
route. The following specific steps were performed:
(1)  Study of polymers: Solubility and release of drug
from MA coprecipitates containing several polymers
at different drug-to-polymer ratios were studied.
Two polymers, with the best results were chosen
for all further investigations;
(2)  Physico-chemical characterization of the coprecipi-
tates: These studies were performed to find possible
drug-polymer interaction;
(3)  Drug release study of semisolid preparations:
Aqueous ionic creams, ointments, and gels con-
taining different concentrations of MA in the form
of coprecipitates in those two selected polymers
were prepared to study the effects of various bases
and drug concentration on the release and top four
cream or ointment and top six gel formulations were
selected from here for the following studies;
(4)  Rheological and stability studies of semisolid prepa-
rations: Rheological properties of the topical for-
mulations were studied to measure thixotropy and
other desirable properties of semisolid materials.
 Pharmaceutical Development and Technology
Stability studies included determination of change
in drug content, viscosity, and pH of the semisolid
formulations;
(5)  The identification of the best topical formulation:
Data from the performed studies was considered to
identify the best topical formulation of MA.
Materials and methods
Materials
Mefenamic acid was kindly supplied by Uni-pharm
Company for Pharmaceuticals (Cairo, Egypt). The other
chemicals were purchased as follows: polyethylene
glycol 400 from Prolabo (Paris, France); polyethylene
glycols (PEG 2000, PEG 4000, and PEG 6000) from Merck
Chemicals Co. (Darmstadt, Germany); polyvinylpyrro-
lidone (PVP K30 and PVP K90) from Fluka Chemie AG
(Buchs, Switzerland); Carbopol® 934 and Carbopol®
940 from Goodrich Chemical Co. (London, UK); beta-
cyclodextrin (β-CD) from CycloLab Ltd. (Budapest,
Hungary); mannitol, methylcellulose 4000, hydroxy-
propyl methylcellulose 4000, Pluronic® F127, and tri-
ethanolamine from Sigma Chemical Co. (Gaithersburg,
MD, USA); urea, sodium hydroxide, disodium hydrogen
phosphate, potassium dihydrogen phosphate, mineral
oil, cetyl alcohol, beeswax, white wax, propylene glycol,
sodium borate, sodium lauryl sulfate, and carboxymeth-
ylcellulose sodium 4000 from Fisher Scientific (Pittsburg,
PA, USA).
Methods
Preparation of coprecipitates
Mefenamic acid coprecipitates containing seven differ-
ent polymers (PEG 2000, PEG 4000, PEG 6000, PVP K30,
PVP K90, mannitol, and urea) at 1:1, 1:2, and 1:4 (w/w)
drug-to-polymer ratios were prepared using coevapora-
tion method. The calculated amounts of MA and each
of the aforementioned polymers were dissolved in 0.1 N
NaOH and the least amount of water, respectively. The
drug solution and the polymer solution were mixed
together and the solvent was evaporated in an oven
at temperature 40–45°C. The obtained coprecipitates
were kept in a desiccator over anhydrous calcium chlo-
ride. The dried mass was pulverized and sieved using a
Labortechnik RX 86, VEB, MLW sieve shaker (Ilmenau,
Germany). The fraction of the powder that passed
through 250 μm sieve and retained on 125 μm sieve was
collected and used for the investigation. Inclusion com-
plex of MA with β-CD was also prepared by the above
mentioned method at 1:1 and 1:2 drug-to-polymer
molar ratios, which correspond to approximately 1:4.7
and 1:9.4 w/w ratios.

Preparation of physical mixtures
Each of the previously mentioned polymers and MA at
the same drug-to-polymer ratios (1:1, 1:2, and 1:4, w/w)
were gently triturated using a glass mortar. The obtained
mixtures were kept in a desiccator over anhydrous cal-
cium chloride, pulverized, and sieved as mentioned
before. The physical mixture of drug with β-CD was
prepared at 1:1 and 1:2 drug-to-polymer molar ratios.
Solubility study of coprecipitates
The equilibrium solubility of MA was determined for
the coprecipitates, physical mixtures, and the drug
alone. An excess amount of the sample to be tested was
added to 10 mL of phosphate buffer of pH 7.4 in 30 mL
screw capped vials. The vials were shaken for 48 h in
a Gallenkamp oscillating thermostatically controlled
shaker (Loughborough, UK) at 37°C. The solution was
filtered through 0.45 μm Millipore filters and the con-
centration of the drug was determined spectrophoto-
metrically using a Pye Unicam, SP6-550 ultraviolet
spectrophotometer (Cambridge, UK) at 285 nm. All
experiments were run in triplicate.
In vitro release of mefenamic acid from coprecipitates
The in vitro release of the pure drug, the coprecipitates,
and the physical mixtures was carried out in an Erweka
USP basket type standard dissolution apparatus (USP
dissolution test apparatus I, version DT Heusenstamm,
Germany). An accurate amount of the prepared systems
equivalent to 100 mg of MA was placed inside the basket
in the dissolution vessel that contained 500 mL of pH 7.4
phosphate buffer at 37°C and the basket was rotated at
100 rpm according to the USP specification.[13] Three mil-
liliter aliquots with replacements were withdrawn at 5, 10,
15, 30, 45, 60, and 90 min. Samples were filtered through
0.45 μm Millipore filters and properly diluted prior to
measuring the absorbance at 285 nm. Each sample was
run in triplicate.
Physico-chemical characterization of coprecipitates
Infrared spectroscopy.  Samples of approximately 2–3 mg
of drug, polymers, or coprecipitates were mixed with KBr
powder and compressed into transparent disc under
pressure and then tested within the range 4000–500 cm−1
in a Shimadzu IR-435 U-04 IR spectrophotometer (Tokyo,
Japan).
Differential scanning calorimetry.  All the materials used
in the infrared spectroscopic study were tested in this
section. Accurately 1.7 mg of fresh samples were encap-
sulated into flat-bottom aluminum pans with crimped-on
lids. The scanning was performed in a Shimadzu DSC
TA-50 ESI DSC apparatus (Tokyo, Japan) at a speed of
10°C/min from 30–300°C in the presence of nitrogen at a
flow rate of 30 mL/min.
© 2011 Informa Healthcare USA, Inc.
Topical formulations of mefenamic acid   499
X-ray diffractometry.  A Shimadzu XD-610 X-ray
­diffractometer (Tokyo, Japan) was used to character-
ize the crystalline phases of the same materials used
in spectroscopic and calorimetric studies. The samples
were exposed to Cu-Kα radiation (40 kV × 30 mA) at a
scan rate of 8°/min. A fixed slit system with the following
slit parameters divergence, 1°; scatter, 1°; and receiving,
0.3 mm was employed. The output was given as intensity
versus 2θ.
Preparation of creams and ointments
Aqueous ionic creams and ointments were prepared by
suspending or dissolving plain MA or MA coprecipitates
in a semisolid base. Two of the USP classes of ointment
bases were used in the study. Those classes were absorp-
tion (water-in-oil emulsion) and water soluble ointment
bases.[14] Oleaginous (hydrocarbon), another class of base
was included in the preliminary study. Drug-to-polymer
ratio in coprecipitates was maintained at 1:4 (w/w). Final
drug concentrations in the creams and ointments were 1,
2.5, 5, and 10%. The composition of the aqueous cream
and ointment bases is shown in Table 1.
Preparation of aqueous creams and ointments containing
absorption base.  The oil phase was melted at 60°C. The
drug or the coprecipitate was dissolved or suspended in
the calculated amount of distilled water and the other
water soluble substances were added in it. The aqueous
phase containing either plain MA or MA coprecipitate
was warmed to about the same temperature of the
oil phase and then added gradually to the oil phase
with continuous stirring until cream or ointment was
formed.
Preparation of ointments containing water soluble base. 
PEG 4000 and cetyl alcohol were melted on water bath
operated at 60°C with continuous stirring. Then PEG 400
containing specific amount of plain MA or MA coprecipi-
tate were added to the melted base. Stirring was contin-
ued until the preparations congealed.
Preparation of gels
Mefenamic acid or its coprecipitates, used at the same
concentrations as in the creams/ointments were dis-
solved or suspended in each gel base. Table 1 illustrates
the types and concentrations of the gel bases in the final
preparation.
Preparation of cellulosic gel bases.  The weighed amount
of carboxymethylcellulose sodium (CMC Na) powder
was sprinkled gently on a vortex in 100 mL beaker con-
taining distilled water and stirred magnetically at high
speed using a MLW, ER10 homogenizer (Prugerate-Werk,
Germany). Stirring was continued until a thin hazy dis-
persion without lumps was formed. Leaving overnight
in the refrigerator was necessary for complete gel dis-
persion. The method was the same for methylcellulose
 500   T.A. Ahmed et al.
Table 1.  Composition of the semisolid bases.
Aqueous ionic cream
Cetyl alcohol 15.0 g Cetyl alcohol
Beeswax 1.0 g White wax
SDS 2.0 g Mineral oil
Propylene glycol 10.0 g Sodium borate
Water 72.0 g Water
Gel bases
Methylcellulose
Carboxymethylcellulose sodium
Hydroxypropyl methylcellulose
Carbopol® 934
Carbopol® 940
Pluronic® F127
(MC) and hydroxypropyl methylcellulose (HPMC) except
the use of boiling distilled water for MC gel preparation
and the use of a portion of hot distilled water at 80°C
for HPMC gel preparation while the remaining amount
of added water was cold and mixing was continued till
smooth homogenous HPMC gel was formed.
Preparation of Carbopol® gel bases.  Carbopol® gels
were prepared by homogenizing 0.5% (w/v) Carbopol®
dispersion in sufficient water by using a magnetic stirrer
for 30 min and leaving it to equilibrate for 24 h. After that,
pH was adjusted to 5–7 with triethanolamine.[15]
Preparation of Pluronic® gel base.  The required amount
of Pluronic® F127 powder was slowly added to cold dis-
tilled water (5–10°C) while maintaining constant agitation
with a magnetic stirrer. The dispersion was left overnight
in a refrigerator to form a clear viscous solution. The
required amounts of plain drug or drug coprecipitates
were dissolved in distilled water at 5–10°C and mixed
with gel when the gel was still liquid. The Pluronic® gels
exhibit thermal behavior and therefore, it was fluid at
lower temperatures.
In vitro release of mefenamic acid from semisolid
preparations
The semisolid formulations were placed onto a watch
glass of 8 cm diameter, spread evenly on its surface and
covered with equal size standard stainless steel 210 µm
mesh wire screen.[16] The watch glass-formulation-
screen sandwich was held together by three equally
spaced binder clips. The assembly was placed at the
bottom of Erweka USP paddle type standard disso-
lution apparatus (USP dissolution test apparatus II,
version DT 600, Heusenstamm, Germany) contain-
ing 500 mL of phosphate buffer solution of pH 7.4,
maintained at temperature of 32 ± 0.5°C, and speed of
50 rpm. The height of the paddle from the surface of
the assembly was adjusted to 2.5 cm. Aliquots of 1 mL
were withdrawn from the release medium at each time
interval at 15, 30, 45, 60, 90, 120, and 180 min. These
 Pharmaceutical Development and Technology
Absorption base Water soluble base
12.5 g PEG 4000 47.5 g
12.0 g PEG 400 47.5 g
56.0 g Cetyl alcohol 5.0 g
0.5 g
19.0 g
Concentration (% w/w)
3
2
3
0.5
0.5
20
were immediately replaced by equivalent volumes of
freshly prepared buffer solutions. Blank experiments
were performed at the same time of test experiments
applying the same condition as that in the test experi-
ment except that, a plain base was used in blank exper-
iment. The amount of the drug released from the bases
was determined spectrophotometrically at 285 nm by
measuring the test samples against blank samples.
Experiments were carried out in triplicate and mean
results were reported.
Kinetic analysis of drug release
The data obtained from the experiments were analyzed
by means of a computer to establish the order of the drug
release. The following linear regression equations were
used.
Ct = Co × kt for zero order kinetics;
ln Ct = ln C0 − kt for first order kinetics;
Q = D ( 2C0 − C s ) C s t for Higuchi model.
In the Higuchi model, ‘Q’ is the amount of drug released
per unit area in time ‘t’, ‘D’ is the drug diffusion coefficient
in the matrix, ‘C0’ is the initial drug concentration in the
matrix and ‘Cs’ is the drug solubility in the matrix. This
equation describes drug release as being linear with the
square root of time ( Q = k t ).
Rheological properties of semisolid preparations
Brookfield LVTD V-II programmable viscometer of
Engineering Laboratories, Inc. (Middleboro, MA, USA)
was connected to a thermostatic water bath adjusted
at 25°C. The viscosity of the plain cream, ointment,
and gel bases and medicated bases containing 1%
MA with PVP K30 and PVP K90 coprecipitates was
determined.
The viscosity measurements were performed on each
sample with spindle 40. About 0.5 g of the cream, oint-
ment, or gel was placed inside the plate and carefully
 Topical formulations of mefenamic acid   501

closed. The experiment was performed by increasing Results and discussion

the spindle speed gradually. As the speed was increased,
torque also increased. The data obtained in the torque Study of polymers
range of 10–90% were taken. Thirty seconds were left
As suggested, coprecipitates of mefenamic acid were
between each two successive speeds. Once the torque
prepared at a temperature relatively lower than the
reached 90%, the speed was reduced gradually, with the
compound’s melting point.[19,20] The solubility of pure
same order as the increasing one, until a torque of 10%
MA in phosphate buffer of pH 7.4 was determined to be
was found.
0.129 mg/ mL. It was found that all the prepared copre-
Rheological parameters including shearing stress, rate
cipitates increased the aqueous solubility of the drug. The
of shear, viscosity, and yield value were directly obtained
solubility of the drug in a coprecipitate was also found to
from program. Complete rheograms was obtained by
be higher than that in the corresponding physical ­mixture.
plotting the rate of shear as a function of the shearing
The solubility data of the coprecipitates and physical
stress. The areas of the hysteresis loops between the
mixtures are presented in Table 2. It is evident that PVP
upward (right side) curves and the downward (left side)
polymers, at all ratios produced the highest solubility.
curves in the rheograms of both plain and medicated
For all polymers, except β-CD, drug solubility increased
bases were determined by cut and weight method using
as the proportion of polymer was increased. For β-CD, a
tressing paper. Farrow’s constant, N was calculated using
1:2 polymer ratio showed lower solubility than 1:1 ratio.
the following equation
This could be due to the saturation of the cyclic polymer
log ’G with drug in the inclusion complex.
N= Using coprecipitates to improve drug solubility is well-
log F known. The mechanism of this could be conversion of the
where ‘G’, ‘F’ and ‘η′‘ are the rate of shear, shearing stress, drug from its crystalline form to amorphous form; reduc-
and non-Newtonian viscosity, respectively.[17] tion of drug particle size causing increase in the specific
surface area of drug particles; encircling drug particles by
Stability studies of semisolid preparations hydrophilic polymers leading to the improvement of drug
Prepared creams, ointments, gels, and the plain bases wettability, and decreases in aggregation and agglomera-
were stored in well stoppered containers in dark at tion of drug particles.[21]
room temperature for one year. They were checked for The prepared coprecipitates also showed faster in vitro
their drug content, viscosity, and pH change bimonthly drug release than the physical mixtures for the respective
throughout the period. The methods used by Tas et al.[18] polymers (Table 3). All polymers, except β-CD produced
to investigate the stability of chlorpheniramine maleate increased dissolution of drug at higher polymer propor-
in gels prepared by different cellulose derivatives were tions. The rank order of polymers in terms of drug release
followed in the present stability studies. from the coprecipitates after 90 min, which is almost
Determination of drug content.  An accurately weighed
Table 2.  Solubility ± standard deviation of mefenamic acid from
quantity of cream, ointment, or gel (about 100 mg each) coprecipitates and physical mixtures (in parentheses) at different
was dissolved in about 50 mL of phosphate buffer saline drug-to-polymer ratios (n = 3).
at pH 7.4. These solutions were quantitatively transferred Solubility (mg/mL)
to volumetric flasks and appropriate dilutions were made Polymer 1:1 (w/w) 1:2 (w/w) 1:4 (w/w)
with the same buffer solution. The resulted solutions PEG 2000 0.322 ± 0.016 0.345 ± 0.005 0.362 ± 0.011
were then filtered through 0.45 μm membrane filters (0.211 ± 0.006) (0.223 ± 0.006) (0.235 ± 0.008)
before subjecting to spectrophotometric analysis for MA PEG 4000 0.342 ± 0.004 0.365 ± 0.005 0.382 ± 0.004
at 285 nm. (0.223 ± 0.004) (0.231 ± 0.004) (0.244 ± 0.006)
PEG 6000 0.352 ± 0.003 0.371 ± 0.005 0.394 ± 0.006
Viscosity measurement.  Brookfield viscometer was (0.228 ± 0.003) (0.239 ± 0.012) (0.250 ± 0.006)
used to measure the viscosity of the prepared creams, PVP K30 0.444 ± 0.009 0.485 ± 0.009 0.586 ± 0.012
ointments, gels, and the plain bases. The spindle was (0.235 ± 0.005) (0.248 ± 0.010) (0.266 ± 0.006)
rotated at 10 rpm. Samples were allowed to settle over PVP K90 0.436 ± 0.007 0.490 ± 0.009 0.602 ± 0.008
30 min at room temperature before the measurements (0.241 ± 0.010) (0.252 ± 0.008) (0.271 ± 0.006)
were taken. Mannitol 0.362 ± 0.008 0.381 ± 0.005 0.400 ± 0.013
(0.220 ± 0.013) (0.231 ± 0.008) (0.255 ± 0.009)
pH measurements.  pH was measured by immersing Urea 0.211 ± 0.007 0.231 ± 0.011 0.261 ± 0.005
the electrode of a Jenway 3050 pH meter (Dunmow, (0.159 ± 0.003) (0.170 ± 0.008) (0.182 ± 0.010)
UK) in 50 g of each sample. The pH meter was calibrated β-CD* 0.401 ± 0.006 0.387 ± 0.005 -
before each use with standard buffered solutions of pH (0.260 ± 0.006) (0.242 ± 0.010)
4, 7, and 10. *Mole to mole ratio; - Not done.

© 2011 Informa Healthcare USA, Inc.

 502   T.A. Ahmed et al.
similar to that of the solubility is as follows: PVP K90 >
PVP K30 > β-CD > PEG 6000 > PEG 4000 > mannitol >
PEG 2000 > urea. PVP polymers resulted in about 99%
drug release from coprecipitates with 1:4 drug-to-poly-
mer ratio after 90 min. This means, when PVP polymers
were used, maximum drug release could be expected
from the coprecipitates.
The two polymers, PVP K90 and PVP K30, which
showed highest solubility and almost complete dissolu-
tion of MA from the coprecipitates were chosen for the
topical preparations to be used at 1:4 drug-to-polymer
ratio. However, before that, these coprecipitates were
subjected to physico-chemical characterization using IR
spectroscopy, DSC, and X-ray diffraction studies to illus-
trate the possible mechanism of enhancing the solubility
and dissolution and to discuss drug compatibility with
the polymers.
Physico-chemical characterization of coprecipitates
Infrared spectroscopy
Almost similar spectra were observed with PVP K30 and
PVP K90 polymers and coprecipitates. Therefore, those
of PVP K90 are shown in Figure 1 as representative data.
Mefenamic acid showed a medium band at 3310.5 cm−1
due to the N-H stretching. In addition, a strong band
due to the C = O stretching of the carboxylate group was
observed at 1650.3 cm−1. The bands appeared at 1575.1,
1506.7, and 1445.9 cm−1 were probably due to the aro-
matic C = C stretching.[22] The infrared spectrum of the
polymer, PVP K90 showed a prominent absorption
band at 2950 cm−1 due to C-H stretching (aliphatic and
alicyclic) in addition to a strong band at 1650 cm−1 due
to C = O stretching of the pyrrolidone ring.[22] The broad
band centered at 3400 cm−1 might be due to moisture
contamination in the polymer.
It is clear from the spectrum of MA-PVP K90 coprecipi-
tates that there were no significant shifts of the absorption
bands of MA and the polymer as all the original bands
were retained at 3314, 1653.1, 1576.4, 1505.7, 1429.8,
and 2951.8 cm−1. Therefore, it can be concluded that the
coprecipitates of MA with PVP polymers were devoid of
any chemical interaction. These findings were in agree-
ment with the results reported by Taylor and Zografi,[23]
Fujii et al.,[19] and Watanabe et al.[24]
Differential scanning calorimetry
According to Figure 2, the DSC thermogram of plain MA
showed two initial peaks at 39.32°C and 174.91°C due to
glass transition and microcrystal formation, respectively,
which were in good agreement with Shibata et al.,[25] who
found the same results with indomethacin. The major
peak at 233.16°C represents the melting. The broad
shoulder after melting may indicate the decomposition
process.
 Pharmaceutical Development and Technology
Mixing MA with PVP K90 in the form of coprecipitates
lowered the endothermic melting process drastically to
76.22°C. This was in agreement with the finding obtained
by Verheyen et al.[26] The folded form (coprecipitate) of a
drug where the drug can be considered folded in poly-
mer shows much lower melting point than the extended
form of the drug (pure drug). Decomposition process
appeared at 252.47°C. The interaction between the two
components of the mixture might have started at about
35°C, as shown by the DSC curve (Figure 2). The cor-
responding values for PVP K30 were 81.26°C, 264.27°C,
and 40°C, respectively (figures not shown). From these
results, it can be concluded that the coprecipitates of
MA with PVP K30 and PVP K90 should be stored at tem-
peratures not exceeding 40 and 35°C, respectively, to
avoid melting of the coprecipitates.
X-ray diffractometry
X-ray powder diffraction was performed in order to
elucidate the physical structure of the drug in the
coprecipitates.[27] Figure 3 explains the X-ray diffraction
pattern of the MA-PVP K90 system in comparison with
plain MA and plain polymer. MA showed high intensi-
ties in the region 6–28° of 2θ, indicating a well defined
crystallinity of such a substance. The diffraction spec-
tra of PVP K90 showed no crystalline structure of such
polymer.
On mixing these polymers with MA, the crystalline
property of the latter was greatly deformed, which were
defined for solid dispersions.[25] PVP K30 showed more
or less similar results (figures not shown). Delneuville
et al.[28] also found that drug-PVP coprecipitates of dithra-
nol showed disappearance of X-ray diffraction peaks of
the drug crystals. The increase in the solubility and dis-
solution of MA from coprecipitates might be attributed
to the change in the crystalline structure of the drug and
can be concluded by higher crystalline deformation
and therefore, these two PVP polymers gave impressive
results in solubility and dissolution studies.
Preparation of topical formulations
The molecular weight and partition coefficient of MA
are comparable to those of some other related NSAIDs,
such as naproxen, diclofenac, flurbiprofen, ketoprofen.[29]
Therefore, topical preparations containing 1, 2.5, 5, and
10% MA were prepared in order to cover all the concen-
trations of the similar NSAIDs available in the market.
Aqueous ionic cream (AC) and absorption (AB) and
water soluble (WS) ointment bases were selected in
this study since these bases produced the best release
among the cream and ointment bases investigated in a
preliminary screening. This finding can be attributed to
significant increase in diffusion coefficient of drug due to
decreased lipophilic content of the base.[30] Preliminary
screening using different concentrations of polymers in
 Topical formulations of mefenamic acid   503

Table 3.  In vitro dissolution ± standard deviation of mefenamic acid from coprecipitates and physical mixtures (in parentheses) at different
drug-to-polymer ratios (n = 3).
Formula Cumulative % release
(Drug:polymer, w/w) 5 min 10 min 15 min 30 min 60 min 90 min
Mefenamic acid 7.12 ± 0.095 11.12 ± 0.172 11.62 ± 0.319 13.89 ± 0.633 23.16 ± 0.801 24.32 ± 0.345
PEG 2000 (1:1) 12.80 ± 0.827 14.19 ± 0.549 28.01 ± 0.788 48.07 ± 0.690 50.95 ± 0.801 58.14 ± 0.335
(7.18 ± 1.147) (14.12 ± 1.439) (25.25 ± 0.707) (30.85 ± 0.681) (37.48 ± 0.935) (49.42 ± 1.327)
PEG 2000 (1:2) 13.66 ± 0.678 18.99 ± 0.753 29.78 ± 1.007 48.87 ± 0.625 61.15 ± 1.048 64.16 ± 0.320
(11.35 ± 1.094) (15.09 ± 0.633) (24.38 ± 1.163) (31.40 ± 0.946) (38.26 ± 1.214) (50.50 ± 1.213)
PEG 2000 (1:4) 14.36 ± 0.374 19.44 ± 0.528 30.93 ± 0.801 49.02 ± 0.377 65.59 ± 0.592 68.10 ± 0.484
(12.04 ± 0.880) (15.68 ± 0.880) (24.57 ± 1.215) (33.55 ± 1.478) (38.64 ± 1.199) (53.36 ± 1.347)
PEG 4000 (1:1) 13.89 ± 0.265 14.74 ± 0.390 36.85 ± 0.731 45.40 ± 0.557 56.98 ± 0.730 68.56 ± 1.158
(13.43 ± 0.600) (14.76 ± 0.628) (20.52 ± 0.396) (34.47 ± 0.618) (36.64 ± 0.677) (50.59 ± 1.269)
PEG 4000 (1:2) 15.96 ± 0.947 19.69 ± 0.532 38.31 ± 0.290 49.56 ± 0.741 70.64 ± 1.095 72.73 ± 0.990
(14.36 ± 0.684) (15.68 ± 1.155) (22.45 ± 1.139) (35.62 ± 0.624) (37.80 ± 0.996) (52.67 ± 1.184)
PEG 4000 (1:4) 18.82 ± 0.847 20.03 ± 0.917 40.20 ± 0.971 49.80 ± 0.740 74.35 ± 0.861 77.82 ± 0.544
(15.82 ± 0.860) (18.61 ± 0.951) (26.15 ± 1.339) (37.94 ± 0.867) (40.42 ± 1.716) (54.29 ± 0.596)
PEG 6000 (1:1) 16.88 ± 0.765 18.53 ± 1.008 38.25 ± 0.953 45.40 ± 1.025 65.78 ± 0.733 67.71 ± 0.584
(10.21 ± 0.988) (14.90 ± 1.286) (22.99 ± 1.320) (34.93 ± 1.286) (40.26 ± 0.927) (52.43 ± 0.606)
PEG 6000 (1:2) 17.89 ± 0.751 20.12 ± 0.734 41.96 ± 0.937 47.94 ± 0.721 68.33 ± 0.588 72.73 ± 0.970
(13.60 ± 0.979) (16.38 ± 0.403) (23.54 ± 1.112) (35.27 ± 0.993) (42.58 ± 1.206) (53.85 ± 0.928)
PEG 6000 (1:4) 19.05 ± 0.885 23.98 ± 0.777 43.19 ± 1.203 49.56 ± 1.053 77.82 ± 0.727 78.52 ± 0.435
(16.45 ± 1.147) (19.61 ± 1.036) (27.75 ± 0.671) (38.09 ± 1.383) (45.95 ± 1.192) (57.67 ± 0.855)
PVP K30 (1:1) 29.88 ± 1.351 31.73 ± 0.525 41.92 ± 1.005 59.76 ± 1.392 88.48 ± 1.437 93.11 ± 1.580
(16.00 ± 0.740) (20.80 ± 0.884) (27.80 ± 0.659) (41.70 ± 0.226) (64.85 ± 1.043) (74.12 ± 1.330)
PVP K30 (1:2) 31.50 ± 1.202 33.58 ± 0.691 51.19 ± 1.051 56.28 ± 0.786 91.49 ± 1.415 94.97 ± 0.555
(17.12 ± 1.434) (22.50 ± 1.177) (30.00 ± 1.478) (32.89 ± 1.060) (67.17 ± 1.146) (75.28 ± 1.267)
PVP K30 (1:4) 39.60 ± 1.065 51.61 ± 1.335 61.61 ± 1.189 64.16 ± 1.317 94.97 ± 1.574 98.68 ± 0.902
(19.45 ± 0.524) (24.84 ± 1.479) (31.20 ± 1.426) (45.00 ± 1.322) (70.64 ± 1.493) (83.38 ± 0.600)
PVP K90 (1:1) 29.18 ± 1.386 31.50 ± 0.406 64.16 ± 1.427 71.80 ± 1.374 80.91 ± 1.431 91.15 ± 1.132
(19.49 ± 0.930) (24.09 ± 1.059) (32.89 ± 0.893) (44.01 ± 1.107) (53.50 ± 0.629) (65.00 ± 0.713)
PVP K90 (1:2) 24.09 ± 0.817 53.97 ± 1.068 66.71 ± 1.160 88.94 ± 1.274 92.54 ± 1.238 95.87 ± 1.502
(22.46 ± 0.879) (24.55 ± 0.720) (35.20 ± 1.692) (46.09 ± 1.606) (60.20 ± 1.421) (74.80 ± 0.969)
PVP K90 (1:4) 32.19 ± 1.034 54.20 ± 1.319 84.54 ± 1.251 90.10 ± 1.198 95.87 ± 1.352 99.19 ± 0.886
(22.68 ± 1.273) (31.03 ± 1.232) (37.52 ± 0.929) (47.48 ± 1.493) (66.49 ± 1.295) (84.20 ± 1.138)
Mannitol (1:1) 16.21 ± 1.085 18.53 ± 1.252 22.93 ± 1.086 24.18 ± 0.436 41.92 ± 1.480 64.85 ± 0.821
(8.10 ± 0.964) (12.97 ± 1.143) (18.23 ± 0.719) (21.36 ± 1.024) (30.00 ± 0.800) (42.85 ± 0.941)
Mannitol (1:2) 17.60 ± 0.923 19.29 ± 0.714 23.99 ± 1.070 28.70 ± 1.111 48.82 ± 0.373 68.76 ± 0.950
(9.10 ± 1.369) (13.26 ± 0.897) (22.35 ± 1.409) (23.97 ± 1.208) (34.06 ± 1.605) (47.68 ± 0.940)
Mannitol (1:4) 18.44 ± 1.195 25.47 ± 1.190 28.47 ± 0.771 32.63 ± 1.064 52.59 ± 1.275 77.06 ± 0.944
(11.80 ± 1.295) (16.03 ± 1.361) (26.42 ± 1.288) (27.27 ± 1.106) (37.37 ± 1.356) (49.53 ± 1.318)
Urea (1:1) 13.53 ± 0.804 19.45 ± 0.761 19.68 ± 0.638 20.84 ± 0.526 24.84 ± 0.923 36.44 ± 0.447
(11.08 ± 1.056) (14.12 ± 1.676) (15.51 ± 1.518) (17.60 ± 1.354) (23.68 ± 1.302) (30.61 ± 1.490)
Urea (1:2) 15.05 ± 1.115 20.51 ± 1.270 22.98 ± 0.877 25.76 ± 1.394 28.53 ± 0.838 39.53 ± 1.247
(11.35 ± 1.201) (14.58 ± 1.335) (16.12 ± 1.152) (18.44 ± 1.191) (25.29 ± 1.460) (34.45 ± 0.981)
Urea (1:4) 19.97 ± 0.932 23.66 ± 0.752 24.36 ± 1.250 30.90 ± 0.830 36.67 ± 1.131 42.37 ± 0.720
(11.55 ± 1.156) (14.81 ± 1.309) (18.28 ± 1.372) (19.75 ± 1.600) (27.37 ± 1.407) (37.37 ± 0.557)
β-CD (1:1)* 26.17 ± 0.497 30.34 ± 0.590 66.71 ± 0.698 68.10 ± 0.862 76.20 ± 0.777 90.33 ± 0.978
(22.23 ± 1.669) (30.11 ± 0.965) (31.73 ± 1.292) (41.29 ± 1.438) (61.29 ± 1.018) (67.17 ± 0.773)
β-CD (1:2)* 27.56 ± 0.735 30.11 ± 0.755 34.97 ± 0.797 57.21 ± 0.326 70.88 ± 0.829 74.12 ± 0.660
(21.77 ± 0.968) (24.55 ± 0.880) (32.19 ± 0.878) (39.60 ± 0.924) (59.60 ± 0.733) (64.62 ± 0.743)
* Mole to mole ratio.

the gel formulations was performed before the present
study. The least concentration of each polymer needed to
form gels (Table 1) was used to prepare the formulations
for dissolution, rheological, and stability studies because
it was found that the drug release decreased with higher
polymer concentrations. One obvious reason for this
would be the increase in viscosity due to the increase
in polymer concentration.[18] It is also possible that at
the higher polymer concentrations the active substance
was trapped by the polymer molecules and was struc-
tured by its close proximity to those polymer molecules.
This increased the resistance to diffusion by more than

© 2011 Informa Healthcare USA, Inc.

 504   T.A. Ahmed et al.

0.1
95

2338.6

2171.5

893.8
Peak 165.15C

703.6
845.9
Onset 157.72C

2371.0
2945.7
2570.5
3711.6

1039.4
Endset 181.84C

573.2
1074.1
90 Peak 252.47C

655.4
29.07C Height −0.071mW Onset
3674.4

31.39C 240.83C
−0.4 Heat −5.68mJ

753.4
−0.058mW Endset 260.42C

1160.5
3649.4

−0.95mJ Height −0.076mW

1319.2
85 Heat −5.46mJ

1372.3
2951.8
3314.0

Peak 76.22C
3445.4

80 Onset 35.16C

1505.7

1285.3
−0.9

1429.8
Endset 110.99C

1576.4

1259.0
Height −1.180mW
Heat −0.34J Coprecipitate
75
Coprecipitate

1653.1
10
70

Heat flow (mW)

90
% Transmittance

5
80

70
Polymer Polymer
0
100
0
Peak 174.91C
1937.0
1798.2
1743.9

814.1

Onset 166.17C
3676.8
3623.3
3658.8
3567.0

700.0
628.3

Peak 39.32C
990.0

584.0
2371.9

893.9 848.5

Height −0.158mW
663.0

522.8

Height −0.174mW
1094.9
1039.2

80 Heat −8.15mJ
542.6

Heat −0.92mJ
1159.7 1186.2

777.1

−5
2567.3
2731.9
2641.1
3310.5

1328.3
3012.1
2973.6
2914.5
2860.0

752.4

60
Peak 233.16C
O OH CH3 −10 Onset 215.93C
1445.9

H Endset 246.76C
1506.7

N CH3 Height −15.950m

40
1575.1

Heat −0.85J

−15 Drug
1255.0
1650.3

20 Drug 0 100 200 300

4000 3500 3000 2500 2000 1500 1000 500 Temperature (ºC)
Wavenumber (cm−1)
Figure 2.  Differential scanning calorimetric thermograms
of mefenamic acid-PVP K90 coprecipitate and the individual
Figure 1.  Infrared spectra of mefenamic acid-PVP K90 coprecipitate
components.
and the individual components.

expected. Additionally, the density of chain structure,

which has been observed in gel microstructure increased
70 Coprecipitate
at the higher polymer concentration and this limits the
active substance’s movement area.[31–34] 0
1000 Polymer
500
Drug release study of topical formulations
Drug
In vitro release of mefenamic acid from creams and 560
Intensity

ointments
A total of 36 cream and ointment formulations of 420
mefenamic acid in AC, AB, and WS bases were studied
250
for drug release. The final concentrations of MA in the
formulations were 1, 2.5, 5, and 10% and the drug was
140
used as coprecipitates of PVP K30 and PVP K90 and
plain drug as the reference. A slight improvement of
0
drug release from the coprecipitates compared to the 0 10 20 30 40 50 60
plain drug was observed. The results obtained from the 2θ (º)

WS bases are shown in Figure 4 as this base showed Figure 3.  X-Ray diffraction patterns of mefenamic acid-PVP K90
the highest improvement in drug release among the coprecipitate and the individual components.

 Pharmaceutical Development and Technology

 Topical formulations of mefenamic acid   505

100 WS base started dissolving after about 5 min as seen

1%
with naked eyes. The base, however, was not completely
90 2.5%
5%
dissolved during the three hour period of study. AC
80 10% formulations started dissolving or mixing with the dis-
70 solution medium after about 15 min and the rate of dis-
Cumulative % release

solution or mixing was slower than WS formulations. AB

60
base was not found to be dissolved. Since in many cases
50 the base showed dissolution to some extent, diffusion of
40 the drug through the bases along with the dissolution of
the bases might have been responsible for drug release
30
from a majority of these formulations.
20 It is important to note that, the release of MA decreased
10 as the concentration of the drug was increased from 1
Plain drug in WS base to 10%. This could be attributed to the increased micro
0
viscosity of the base at higher concentration of the added
100
1% solid drug. These results are in agreement with previous
90 2.5% findings with diclofenac.[35] WS and AC bases produced
5%
80 10%
higher drug release than AB bases and therefore, were
used for rheological and stability studies using the drug
70
Cumulative % release

at 1% concentration.
60

50 In vitro release of mefenamic acid from gels

Seventy two gel formulations using six polymers (Table 1)
40
containing plain drug or drug in either PVP K30 or PVP
30 K90 coprecipitates were studied for drug release. Used
20 drug concentrations were 1, 2.5, 5, and 10%. It was
observed that the in vitro release of MA from the copre-
10
PVP K30 coprecipitates in WS base cipitates was higher than the plain drug for all studied
0 gel polymers. The drug release characteristics of all gel
100 formulations were different from one another. For both
1%
90 2.5% PVP K30 and PVP K90 coprecipitates, the extent of drug
5% release of MA from the gel formulations could be arranged
80 10% in the descending order as follows: MC > Carbopol® 934
Cumulative % release

70 > HPMC > Carbopol® 940 > Pluronic® F127 > CMC Na.
60 Drug release from gel formulations was thought to be
50
controlled by the interaction between MA and the bases
through ionic and hydrogen bonding. CMC Na formu-
40 lations exhibited the slowest release of drug due to the
30 presence of the most number of sites for drug interactions
20
among the gel base polymers. The carboxylate groups
of CMC Na were thought to bind with the secondary
10 amine of mefenamic acid while the sodium ion could be
PVP K90 coprecipitates in WS base
0 bonded to the carboxylic acid group of the drug through
0 30 60 90 120 150 180 ionic bonds. The secondary alcohol groups of CMC Na
Time (min) could form hydrogen bonding with the carboxylic acid
Figure 4.  In vitro release of mefenamic acid from ointments contain-
group of the drug.[18] In contrast, the secondary alcohol
ing water soluble base. and methoxy groups of methylcellulose could only form
hydrogen bonding with the secondary amine and the car-
studied bases. As the lipophilic content of the bases boxylic acid groups of the drug and hence, showed less
increased, the release of drug declined, which could interaction compared to CMC Na. HPMC, on the other
be due to slower diffusion of drug through the bases in hand, is more reactive than MC because in addition to
the following order: AB < AC < WS. This expected result the secondary alcohol and methoxy groups, it contains
also suggested that there was minimal or no unusual hydrophilic isopropyl alcohol groups, which could form
chemical interaction between the drug and the base hydrogen bonding with the amine and carboxylic acid
components. groups of the drug as well. That could be the reason for

© 2011 Informa Healthcare USA, Inc.

 506   T.A. Ahmed et al.

HPMC showing slower release than MC. Therefore, there Like the cream/ointment formulations, as the con-
was least drug-MC interaction leading to maximum drug centration of the MA increased, drug release decreased.
release among the gel formulations. Carbopol® 934 exhib- MC based gels of 1% MA and PVP K90 showed more than
ited better drug release than Carbopol® 940 probably due 90% release after 1 h and almost 100% release after 2 h.
to the less viscosity of the former. The data obtained with PVP K30, on the other hand, produced 85% and 92%
MC gels are shown in Figure 5 as the increase in drug release at those time points, respectively. MC, HPMC,
release with MC samples was the most prominent. and Carbopol® 934 produced higher drug release than the
other polymers and therefore, were used for rheological
100 and stability studies using the drug at 1% concentration.
1%
2.5%
It was also noted that, the release profile of MA from
90
5% gel bases, in general was better than that from the cream
80 10% and the ointment bases. The solubility of the base in the
dissolution medium was thought to be responsible for
Cumulative % release

70
the differences in drug release.[30]
60

50 Kinetic data of mefenamic acid release

40 In order to develop an ideal kinetic model to interpret
the diffusion data in terms of meaningful parameters,
30
various kinetic models including zero order, first order,
20 and Higuchi diffusion were applied to obtain the best fit
10 of the results. WS, AC, MC, HPMC, and Carbopol® 934
Plain drug in MC base
0
bases were chosen to study the kinetic behavior of drug
100 release. The obtained data are presented in Table 4. The
1%
in vitro release of the MA coprecipitates followed either
90 2.5%
5% first-order or Higuchi diffusion model.
80 10%
70
Cumulative % release

Rheological properties of topical formulations

60
Aqueous ionic creams and ointments containing MA
50 coprecipitates in WS base and the plain bases showed
40 plastic flow in the rheological study. The results are
reported in Table 5. Yield value of a plastic system repre-
30
sents the system’s relation to Newtonian flow according
20 to the following equation.
10
PVP K30 coprecipitates in MC base F−f
0 U=
100 G
1%
90 2.5% ‘U’ is the plastic viscosity and ‘f’ is the yield value of the
5% non-Newtonian system.[17] Plastic flow is found in floc-
80 10%
culated suspensions where adjacent particles are bonded
70
to each other by van der Waals’ forces, which must be
Cumulative % release

60 broken down before any flow can be observed. Yield

50 value is the minimum force required to break this bond.
As the value of ‘f’ increases, the sample becomes more
40
different from a Newtonian system. Ointments contain-
30 ing water soluble base and MA-PVP K90 coprecipitate
20 produced the highest viscosity and yield value among
the creams and the ointments. This could be due to the
10
PVP K90 coprecipitates in MC base presence of larger polymers, e.g. PEG 4000 and PVP K90
0 in the preparation.
0 30 60 90 120 150 180
All the cream and ointment preparations and their
Time (min)
bases were also found to have thixotropic behavior. The
Figure 5.  In vitro release of mefenamic acid from gels containing area of hysteresis loop can be used as a measurement of the
methylcellulose base. thixotropic behavior of a formulation.[17] Table 5 presents

 Pharmaceutical Development and Technology

 Topical formulations of mefenamic acid   507

Table 4.  Kinetic parameters of mefenamic acid release from different topical ointment and gel bases formulations.
Correlation coefficient (r)
PVP K30 PVP K90
Formula Zero First Higuchi Zero First Higuchi
Aqueous ionic cream 0.98965 −0.99125 0.98804 0.98358 −0.98997 0.99326
Water soluble base 0.97115 −0.97341 0.97562 0.91722 −0.92838 0.96190
Gel base
MC 0.89493 −0.98825 0.95057 0.85827 −0.95417 0.92503
HPMC 0.82727 −0.91409 0.89826 0.78144 −0.86650 0.86090
Carbopol® 934 0.89830 −0.97914 0.95168 0.84070 −0.95878 0.90649

the area of hysteresis loop of the samples. Ointments con-

taining MA-PVP K90 coprecipitate in WS base produced Table 5.  Rheological properties of 1% mefenamic acid creams and
ointments.
the highest thixotropy among the samples. The complete
Yield value
rheograms of WS base and its ointments with MA-PVP K90 Maximum Minimum Hysteresis (dyne/
and MA-PVP K30 are presented in Figure 6. Formula viscosity(cp) viscosity(cp) loop area (cm2) cm2)
All the gel preparations and plain bases were found to Aqueous ionic cream
be pseudoplastic. Some of those also showed thixotropic Plain base 3660 795 1.735 393
character. The results are shown in Table 6. Gel formula- PVP K30 4764 999 1.710 422
tions containing MA-PVP K90 coprecipitates in HPMC and PVP K90 7610 3617 1.677 690
MC bases were on the top in terms of thixotropy. Figure 7 Water soluble
illustrates the rheograms for systems containing MC as a Plain base 8155 2511 1.793 914
representative of the gel preparations. Thixotropy is a desir- PVP K30 12134 7613 2.516 1160
able property in liquid pharmaceutical systems because PVP K90 19678 15429 5.460 1311
these systems retain their high consistency in the con-
tainer, yet can be poured from the containers precisely and
35
spread on the skin easily.[17] Besides, thixotropy improves
product stability by decreasing the rate of sedimentation, 30
which might be crucial for parenteral products.
Rate of shear (sec−1)

25

20
Stability studies of topical formulations
15
Stability studies with topical formulations containing
10 Base
mefenamic acid coprecipitates in PVP K30 and PVP K90 PVP K30
were carried out to detect any changes in drug content, 5 PVP K90
viscosity, and pH of the preparations through one year.
0
The results are shown in Tables 7–9. All of the semisolid 1000 1200 1400 1600 1800 2000 2200 2400 2600
samples showed excellent results in these studies. Drug Shearing stress (dyne/cm2)
degradation was found to be in the range 3.35–8.80%
after one year. Viscosity change compared to the initial Figure 6.  Rheograms of water soluble ointment base and ointments
containing water soluble base, mefenamic acid, and PVP polymers.
viscosity was in the range 0.25–11.71%, while pH changed
0.03–0.35 unit only. In all cases, HPMC and MC showed
Identification of the best topical formulation
the smallest changes in these parameters, 4.3%, 1.1%, and
0.05 units for drug content, viscosity, and pH, ­respectively. Among the studied polymers, PVP K90 and PVP
PVP K90 and PVP K30 showed very similar data. K30 produced the greatest solubility and dissolu-
Analysis of the drug content results showed that drug tion of mefenamic acid from the coprecipitates at 1:4
degradation probably followed zero-order process for drug-to-polymer ratio and was therefore used for the
all the tested cream, ointment, and gel preparations preparation of cream, ointment, and gel formulations
(Table 10). The shelf lives (t90%) were determined by cal- containing different bases. The bases for cream and
culating the time required to degrade 10% of the drug in ointment formulations were selected based on the
the preparations. Shelf lives, which interpret the lengths drug release study in a preliminary screening. Some
of time through which the formulations comply with the common gel bases were screened to identify the lowest
official requirements of drug contents, were found to be concentrations at which the bases could form gels and
more than two and half years for HPMC gels and about the corresponding concentrations were used in the for-
two years for MC gels. mulations. Various concentrations of drug were used in

© 2011 Informa Healthcare USA, Inc.

 508   T.A. Ahmed et al.

the topical formulations and it was found that ­maximum
release was obtained when the drug concentration was
the lowest (1%). WS and AC bases were the top two bases
in terms of good drug release from cream and ointment
formulations. Among the gel bases, MC produced the
highest drug release followed by HPMC and Carbopol®
934. As a general rule, gel formulations were better than
cream and ointment formulations in terms of drug
release. Rheological and stability studies were conducted
using aqueous ionic creams and ointments in WS base
containing 1% drug and gels containing 1% drug in MC,
HPMC, and Carbopol® bases. Ointments containing
WS base had higher viscosity and thixotropy than those
containing the other ointment and cream. Gels contain-
ing HPMC and MC showed the highest thixotropy. In all
these cases, PVP K90 was found to be slightly better than
PVP K30. Stability study suggested the least changes in
drug content, viscosity, and pH was evident when HPMC
was the base. The results from MC were very compara-
ble. Stability study could not differentiate PVP K90 from
PVP K30.
Based on these evidences, it could be inferred that a
gel formulation with either HPMC or methylcellulose
base containing 1% mefenamic acid as PVP K90 or PVP
K30 coprecipitates at 1:4 drug-to-polymer ratio would
yield desired in vitro release and would possess good
rheological properties and be stable for about two years.
Mefenamic acid in methylcellulose base as PVP K90
coprecipitates, however, could be considered to be the
best formulation in this study.
Conclusions
Topical formulations of mefenamic acid were studied for
drug release, rheological properties, and stability of the
products. PVP K90 and PVP K30 coprecipitates were found
to be suitable to improve drug solubility and dissolution.
HPMC and methylcellulose were the most preferable
bases on the basis of drug release, rheological properties,
and stability of the product. Mefenamic acid at 1% con-
centration was able to show the maximum drug release.

Table 6.  Rheological properties of 1% mefenamic acid gels.

35
Maximum Minimum Hysteresis Farrow’s
Formula viscosity(cp) viscosity(cp) loop area (cm2) Constant 30
MC
Rate of shear (sec−1)

25
Plain base 802 324 0 2.646
PVP K30 762 251 0 4.726 20
PVP K90 1195 513 2.401 1.563
15
HPMC
Plain base 236 114 0.954 1.542 10 Base
PVP K30 863 426 1.118 1.328 PVP K30
5 PVP K90
PVP K90 1709 1005 4.803 1.333
Carbopol® 934 0
0 200 400 600 800 1000 1200
Plain base 3157 947 2.171 4.378
Shearing stress (dyne/cm2)
PVP K30 854 241 0 7.298
PVP K90 1160 358 2.220 2.022 Figure 7.  Rheograms of methylcellulose gel base and gels containing
methylcellulose base, mefenamic acid, and PVP polymers.

Table 7.  Mefenamic acid contents ± standard deviations of the formulations through one year of stability study (n = 3).
% Content
Formulation 0 mo 2 mo 4 mo 6 mo 8 mo 10 mo 12 mo
Cream/ointment
AC-PVP K30 99.99 ± 0.008 99.30 ± 0.286 97.80 ± 0.791 96.00 ± 0.423 95.20 ± 0.067 93.35 ± 0.565 91.65 ± 0.315
AC-PVP K90 99.95 ± 0.029 98.65 ± 0.477 97.45 ± 0.427 96.70 ± 0.367 95.45 ± 0.518 93.20 ± 0.407 91.20 ± 0.193
WS-PVP K30 99.89 ± 0.099 98.95 ± 0.445 98.25 ± 0.340 97.40 ± 0.083 96.60 ± 0.452 94.25 ± 0.785 93.55 ± 0.375
WS-PVP K90 100.00 ± 0.102 98.80 ± 0.339 98.10 ± 0.326 97.25 ± 0.364 96.35 ± 0.485 94.10 ± 1.146 93.50 ± 0.528
Gel
MC-PVP K30 99.96 ± 0.050 99.60 ± 0.438 99.15 ± 0.202 98.25 ± 0.521 97.50 ± 0.436 96.45 ± 0.509 95.75 ± 0.347
MC-PVP K90 100.00 ± 0.088 99.95 ± 0.033 98.85 ± 0.354 98.10 ± 0.259 97.35 ± 0.333 96.30 ± 0.399 95.70 ± 0.524
HPMC-PVP K30 99.98 ± 0.016 99.50 ± 0.407 98.98 ± 0.424 98.50 ± 0.283 97.90 ± 0.758 97.10 ± 0.854 96.65 ± 0.662
HPMC-PVP K90 99.94 ± 0.076 99.40 ± 0.320 99.20 ± 0.323 98.50 ± 0.397 97.82 ± 0.320 97.05 ± 0.850 96.45 ± 0.815
Carbopol® 100.00 ± 0.033 99.35 ± 0.205 98.65 ± 0.492 97.40 ± 0.462 96.10 ± 0.743 94.50 ± 0.466 92.10 ± 0.373
934-PVP K30
Carbopol® 99.97 ± 0.060 99.88 ± 0.049 98.30 ± 0.574 97.40 ± 0.616 96.00 ± 0.595 94.25 ± 0.899 92.00 ± 1.002
934-PVP K90

 Pharmaceutical Development and Technology

 Topical formulations of mefenamic acid   509

Table 8.  Viscosity ± standard deviation of mefenamic acid formulations through one year of stability study (n = 3).
Viscosity (cp)
Formulation 0 mo 2 mo 4 mo 6 mo 8 mo 10 mo 12 mo
Cream/ointment
AC-PVP K30 1400 ± 53.467 1423 ± 40.133 1437 ± 36.359 1440 ± 35.814 1465 ± 27.362 1471 ± 27.435 1485 ± 23.791
AC-PVP K90 6095 ± 68.838 6110 ± 56.680 6119 ± 56.680 6125 ± 56.291 6138 ± 58.839 6149 ± 61.731 6162 ± 60.647
WS-PVP K30 9005 ± 12.754 9009 ± 12.961 9011 ± 11.576 9015 ± 9.933 9023 ± 10.801 9035 ± 16.391 9046 ± 16.753
WS-PVP K90 16890 ± 53.597 16892 ± 54.240 16899 ± 57.155 16901 ± 56.291 16910 ± 55.875 16921 ± 63.645 16932 ± 65.975
Gel
MC-PVP K30 455 ± 5.354 456 ± 4.546 458 ± 3.559 458 ± 2.944 459 ± 3.559 459 ± 2.625 460 ± 3.559
MC-PVP K90 785 ± 5.888 785 ± 6.976 789 ± 5.715 789 ± 5.888 792 ± 4.967 793 ± 6.377 793 ± 5.715
HPMC-PVP K30 594 ± 4.320 592 ± 3.559 592 ± 4.546 591 ± 4.320 591 ± 5.354 590 ± 5.354 590 ± 4.899
HPMC-PVP K90 1352 ± 4.967 1355 ± 5.099 1355 ± 4.320 1356 ± 5.099 1356 ± 4.243 1357 ± 4.320 1357 ± 3.742
Carbopol® 934-PVP K30 427 ± 3.559 421 ± 1.633 416 ± 2.944 409 ± 3.266 401 ± 2.160 394 ± 0.816 377 ± 2.944
Carbopol® 934-PVP K90 545 ± 3.559 540 ± 3.266 529 ± 2.828 521 ± 3.742 512 ± 3.266 501 ± 2.944 484 ± 2.160

Table 9.  pH Values of mefenamic acid formulations through one year of stability study (n = 3).
pH
Formulation 0 mo 2 mo 4 mo 6 mo 8 mo 10 mo 12 mo
Cream/ointment
AC-PVP K30 7.41 ± 0.026 7.36 ± 0.037 7.35 ± 0.033 7.33 ± 0.034 7.31 ± 0.034 7.30 ± 0.029 7.30 ± 0.034
AC-PVP K90 7.45 ± 0.029 7.41 ± 0.037 7.41 ± 0.029 7.40 ± 0.037 7.38 ± 0.033 7.36 ± 0.025 7.35 ± 0.021
WS-PVP K30 2.25 ± 0.043 2.27 ± 0.028 2.29 ± 0.024 2.30 ± 0.024 2.33 ± 0.026 2.37 ± 0.016 2.40 ± 0.014
WS-PVP K90 2.25 ± 0.033 2.28 ± 0.041 2.30 ± 0.039 2.31 ± 0.045 2.33 ± 0.043 2.38 ± 0.036 2.40 ± 0.026
Gel
MC-PVP K30 7.28 ± 0.019 7.28 ± 0.012 7.27 ± 0.016 7.27 ± 0.017 7.25 ± 0.014 7.24 ± 0.017 7.24 ± 0.016
MC-PVP K90 7.31 ± 0.022 7.31 ± 0.017 7.30 ± 0.025 7.29 ± 0.024 7.29 ± 0.029 7.28 ± 0.019 7.28 ± 0.026
HPMC-PVP K30 7.71 ± 0.045 7.70 ± 0.031 7.70 ± 0.034 7.68 ± 0.029 7.67 ± 0.026 7.67 ± 0.033 7.66 ± 0.026
HPMC-PVP K90 7.66 ± 0.036 7.65 ± 0.028 7.65 ± 0.040 7.64 ± 0.034 7.64 ± 0.040 7.62 ± 0.045 7.62 ± 0.042
Carbopol® 934-PVP K30 7.80 ± 0.037 7.84 ± 0.037 7.88 ± 0.029 7.92 ± 0.034 7.96 ± 0.029 7.99 ± 0.024 8.03 ± 0.029
Carbopol® 934-PVP K90 7.85 ± 0.042 7.88 ± 0.041 7.95 ± 0.029 7.99 ± 0.025 8.10 ± 0.037 8.16 ± 0.051 8.20 ± 0.029

could be used in further study to develop topical formu-

Table 10.  Kinetic parameters of mefenamic acid degradation in
lations that would be able to eliminate ­gastro intestinal
­formulations through one year.
Correlation coefficient (r)
disorders of the drug through oral route.
Formulation Zero First Second t90% (years)
Cream/ointment
AC-PVP K30 0.99652 −0.99617 0.99566 1.11
Acknowledgments
AC-PVP K90 0.98179 −0.97986 0.97782 1.14
WS-PVP K30 0.97818 −0.97706 0.97590 1.47 The authors like to thank Dr Kristopher Virga of Irma Lerma
WS-PVP K90 0.98066 −0.97965 0.97860 1.48 Rangel College of Pharmacy of Texas A&M University Health
Science Center for his useful contribution in explaining the
Gel
MC-PVP K30 0.99568 −0.99538 0.99506 2.08
drug releasing behavior of the formulations.
MC-PVP K90 0.99790 −0.99752 0.99771 1.97
HPMC-PVP K30 0.99676 −0.99657 0.99636 2.85
Declaration of interest
HPMC-PVP K90 0.99142 −0.99115 0.99087 2.67
Carbopol® 0.98327 −0.98123 0.97907 1.17
The authors report no conflicts of interest. The authors
934-PVP K30
0.99070 −0.98914 0.98742 1.10
alone are responsible for the content and writing of the
Carbopol®
934-PVP K90 paper.

A topical gel formulation of 1% mefenamic acid in HPMC

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