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Vol 2|Issue 2| 2012 |46-53.

Asian Journal of Pharmaceutical Science & Technology


e-ISSN: 2248 – 9185
www.ajpst.com Print ISSN: 2248 – 9177

FORMULATION AND EVALUATION OF MEFENAMIC ACID


TABLETS BY USING MODIFIED STARCH
Amaravathi Vikram*, S Firoz, D Kishore, Y Chandra Mouli, T Venkataramudu
Department of Pharmaceutics, Sree Vidyanikethan College of Pharmacy, A.Rangampet, Tirupati- 517 102, India.

ABSTRACT
The objective of the present research work is to enhance the dissolution profile of the mefenamic acid by Modified
Starch. Potato starch citrate is prepared as a disintegrating agent and as a noval carrier for the solid dispersions. Starch citrate was
prepared by reacting the citric acid with starch at elevated temperature. Starch citrate was exhibited good flow properties and it
had good swelling property without pasting when heated in water was considered to be promising excipient. Starch citrate was
characterized by Fourier transform infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC) and X-ray diffraction
(XRD) and these results were suggesting that structure of starch had been modified. Mefenamic acid is a non-steroidal anti-
inflammatory drug belongs to the Biopharmaceutics classification system (BCS) class II drug. Dissolution rate is the rate
determining step in the bioavailability of the mefenamic acid. Tablets of four different batches each containing 100 mg of
mefenamic acid were prepared by wet granulation and direct compression method using starch citrate, starch citrate-mafanamic
acid sloid dispersions, microcrystalline cellulose and lactose. Prepared tablets were characterized by Fourier transform infrared
spectroscopy (FTIR), Flow properties, Drug content, Hardness, friability, In-vitro dissolution studies. Results of the Fourier
transform infrared spectroscopy were revealed that there were no interactions between the drug and polymer. Dissolution
parameters of mefenamic acid were found to be improved in tablets prepared by using starch citrate as direct compressible and
disintegant, starch citrate-mefenamic acid solid dispersions when compared to tablets prepared by using microcrystalline cellulose
and lactose. It was concluded that starch citrate is a promising excipient for tablet formulation and also as a carrier for solid
dispersions for enhancing the dissolution rate of poorly water soluble drugs.

Key words: Mefenamic acid, Starch citrate, Biopharmaceutics classification system, Dissolution rate.

INTRODUCTION dendrimers [4]. Although a variety of carriers are available


Nearly about 40% of the newly discovered drugs for the improvement of dissolution profile of the drugs
are lipohilic and failed to reach market due to the poor water continues development of new carriers is needed. Chowdary
solubility [1]. Solubility and dissolution rate is the rate et al [5, 6] has reported starch citrate is as a disntegrant in
determining step for bioavailability of the BCS class II tablet formulation and also a noval carrier for solid
drugs. The bioavailability problem with BCS class II drugs dispersions.
can be overcome by increasing the solubility and dissolution Mefenamic acid is a NSAID belongs to the BCS
rate of the drug in the gastrointestinal fluids [2]. Various class II drug. Dissolution rate is the rate determining step in
pharmaceutical formulation technologies are being the bioavailability of the Mefenamic acid. The main aim of
developed for the solubility and dissolution rate of poorly the present research work is preparation of the potato starch
water soluble drugs such as Micronization, Super critical citrate as a disintegrating agent and as a noval carrier for the
fluid process, Solid dispersions, Solid solutions, solid dispersions. The dissolution profile of the Mefenamic
Sonocrystalisation, Nano suspension, Co solvency, acid has been improved by using starch citrate. Tablets of
Hydrotropy etc [3]. four different batches each containing 100mg of mefenamic
There are numerous carriers available for acid were prepared by wet granulation and direct
enhancement of the solubility and dissolution rate such as compression method using starch citrate, starch citrate-
super disintegrants, polymers, cyclodextrins, carbohydrates, mafanamic acid sloid dispersions, microcrystalline cellulose
surfactants, hydrotropes, polyglycolized glycerides, acids, and lactose. Solid dispersions were prepared by solvent

Corresponding Author: Amaravathi Vikram E-mail: amaravathi.vikram@gmail.com

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evaporation method [7]. The prepared tablets were compressibility index of starch citrate were determined
characterized by Fourier transform infrared (FTIR) based on method of chowdary et al [8].
spectroscopy, Flow properties, Drug content, Hardness,
friability, In-vitro drug release. Preparation of Solid Dispersions
Solid dispersions of Mefenamic acid were prepared
MATERIAL AND METHODS by solvent evaporation method. The solid dispersions were
Mefenamic acid was a gift sample from AtoZ prepared in 1:2 ratio of drug: carrier. Required amount of
pharmaceuticals, Chennai, Potato starch and Methanol were Mefenamic acid was taken into a dry mortar and add
purchased from S.D. Fine Chem. Ltd, Mumbai, and Citric sufficient amount of methanol to get clear drug solution.
acid was purchased from Microfine chemicals. All other Starch citrate was then added and mixed. The thick slurry
chemicals and solvents used were of analytical grade. was kneaded for complete evaporation of methanol and then
dried at 55oC until dry. The dried mass was pulverized and
Preparation of Starch Citrate sieved through mesh no. 80 and stored in desicator.
Potato Starch citrate was prepared based on the
method of K.P.R. Chowdary et al [5, 7]. 20gm of the citric Drug content
acid was dissolved in 20ml of the distilled water. The pH of 50mg equivalent of Mefenamic acid was weighed
the citric acid solution was adjusted to 3.5 with 10M sodium and transfer in to 50ml of volumetric flask. Methanol was
hydroxide solution and finally the volume of the solution added and mixed the contents thoroughly to dissolve the
was made up to 50ml by adding distilled water. The citric drug from the solid dispersions and kept aside for 1hr. The
acid solution was mixed with 50gm of potato starch in a solution was filtered. From the filter solution 1ml was
stain less steel tray and conditioned for 16hr at room withdrawn into 100ml volumetric flask. The volume was
temperature (280C). The tray was then placed in a hot air made up to 100ml with methanol and assayed at 279nm for
oven and dried at 600C for 6hr. the resulting mixture was Mefenamic acid.
ground and further dried in hot air oven and dried at 130 0C
foe 2hr. From the dried mixture the unreacted citric acid Preparation of mefenamic acid tablets
was removed by washing the product with distilled water. Mefenamic acid tablets were prepared by using
The washed product was dried at 50 0C to remove pure drug and solid dispersions (1:2) by wet granulation and
water/moisture completely. The dried starch citrate was dry compression method using starch citrate,
ground and sized. microcrystalline cellulose as direct compressible vehicle.
MF1, MF2 batches were formulated by direct compression
Characterization of Starch Citrate method and MF3, MF4 batches were formulated by wet
Fourier transform infrared (FTIR) granulation method. Tablets of four different batches each
The FTIR spectra of starch, citric acid and starch containing 100mg of mefenamic acid were as per formula
citrate were obtained on a Thermo-IR 200 FTIR given table.1.
Spectrophotometer. The KBr pellet technique was used to
prepare the samples. The spectrum was recorded in the Direct compression method
spectral region from 4000 to 400cm-1. All ingredients were weighed as per formula given
in table and passed through sieve no 40. The ingredients
Differential scanning calorimetry (DSC) were blended for sufficient time to get uniform mixing of
DSC analysis of the starch, citric acid and starch ingredients in a closed polyethylene bag. The powdered
citrate were performed using Mettler Toledo DSC 822e. The blend was compressed in to tablets using rotary punch tablet
samples were weighed and encapsulated in a flat bottomed machine.
aluminum pans. Liquid nitrogen was used as coolant. The
samples were scanned at 100C/min over temperature range Wet granulation method
of 0-3000C. Granules were prepared by using acacia as binder
and water as granulating liquid. All ingredients were
X-ray diffraction (XRD) weighed and mixed for sufficient time to get uniform blend
The solid state properties of the starch and starch by following geometric dilution technique. Water was then
citrate were carried by X-RD by using XPERT-PRO X ray added and mixed thoroughly to obtain a dough mass. The
diffractometer. The diffraction pattern was recorded at room dough mass was then passed through sieve no 12 to get wet
temperature over a range 3 to 80 (2θ). granules. The wet granules were dried at 600C for 2 hours.
The dried granules were again passed through sieve no 16.
Physicochemical properties Magnesium steerate, talc was then added to granules and
The physicochemical properties like solubility, pH, mixed thoroughly. The granules were compressed in to
melting point, viscosity, swelling index, test for gelling tablets using rotary punch tablet machine.
property, density, bulk density, angle of repose,

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Evaluation
Flow properties Physicochemical properties
Flow properties of prepared tablet blend were Physicochemical properties of the starch citrate
evaluated by angle of repose, carr’s index, hausner’s ratio. were shown in the Table.2. Native potato starch was found
Angle of repose was calculated by fixed funnel method. to be simple granules (round and polygonal) in shape. The
Tapped and bulk densities were used for calculation of starch granules consist of semicrystalline structure [9]. The
carr’s index, hausner’s ratio. prepared starch citrate was found to be off white color and
semicrystalline nature. The semicrystalline nature further
Fourier transform infrared (FTIR) conformed by DSC. The melting point of the starch citrate
The FTIR spectra of starch citrate, Mefenamic acid was determined by using meting point apparatus. Native
and solid dispersions were obtained on a Thermo-IR 200 starch and starch citrate was not having any meting point
FTIR Spectrophotometer which was employed to but charred at 2380C, 2220C. The results of DSC further
characterize the possible interactions between the drug and conformed that the native starch and starch citrate does not
carrier in the solid state. The KBr pellet technique was used having melting point. Native starch was hydrolyzing upon
to prepare the samples. The spectrum was recorded in the heating and converted to gel/ paste and it was not found in
spectral region from 4000 to 400cm-1. case of the starch citrate. The swelling property of the starch
citrate in water was compared with starch and it was found
Evaluation of tablets that starch citrate had 1100% swelling in water. Starch
The prepared tablets were evaluated for weight citrate was found to be insoluble in water, aqueous buffers
variation, disintegration time, hardness, friability. Hardness of pH 1.2, 4.5, 7.4 and organic solvents. Starch citrate was
and friability was determined by using “monsanto hardness exhibited good flow properties.
tester”, roche fribilator respectively. Disintegration time Chemically modified starch had good swelling
was determined by using disintegration apparatus (model property without pasting when heated in water was consider
TDL-082 electrolab), water as a testing liquid. to be promising carrier for solid dispersions for enhancing
the dissolution rate of poorly water soluble drugs.
Drug content
20 tablets from each batch of prepared tablets were Fourier transform infrared spectroscopy
used for determination of drug content. The 20 tablets were FTIR spectra of the starch, citric acid and starch
weighed and powdered. From the tablet powder, 100 mg citrate were shown in Fig.3. The starch shows significant
equivalent was weighed and transfer in to 100ml of peaks at 3214.29 cm-1 indicates OH Stretching, 2920.80 cm-
1
volumetric flask. Methanol was added and mixed the . The starch citrate shows significant peaks at 3379.37 cm-1
contents thoroughly to dissolve the drug and kept aside for indicates OH Stretching, 1705.09 cm-1 indicates C=O
1hr. The solution was filtered; the filter solution was diluted stretching, 1146.86 cm-1 indicates C-O-C stretching. The
suitably and assayed at 279nm for mefenamic acid using C=O stretching, C-O-C stretching characteristic bonds were
UV. absent in the starch.

In-vitro dissolution study Differential Scanning Calorimetry


In-vitro dissolution studies were carried for an The DSC thermograms of the starch, citric acid and
prepared batches of tablets by using USP XXIV type II starch citrate were shown in the Fig.4. There was no
apparatus. Dissolution studies were carried at temperature endothermic peaks were observed in starch and starch
370C±0.50C and the paddle rotation speed of 50rpm using citrate. The citric acid was showing the melting point at
7.4 phosphate buffer as dissolution medium. A sample of 156.560C. The results of the DSC conformed that the
5ml was withdrawn at different intervals of time up to 60 structure of the starch and starch citrate were not totally
minutes and 5ml of fresh drug free dissolution medium was crystalline in nature.
added to replace the sample that was withdrawn. Samples
were filtered (0.45µ membrane filter) and diluted suitably X-ray diffraction
and analysed for mfenamic acid at 279nm using UV. The The X-ray diffractogram pattern of potato starch
dissolution experiments were performed in triplicate. and potato starch citrate were shown in the fig.5. The X-ray
diffraction studies can be used to predict the crystallinity of
RESULTS AND DISCUSSION the potato starch and potato starch citrate. The XRD of the
Starch citrate potato strach showed intense peaks at 2θ values of 5.881,
Citric acid can form reactive anhydride upon 16.945, 17.024, 17.123, 17.262, 17.319, 17.433, 17.6,
heating by loosing water molecule. The reactive anhydride 17.739. The potato starch citrate showed intense peaks at
can react with starch which is present in the reaction 16.686, 16.806, 17.101, 17.366, 17.471, 17.799 and 18.057.
mixture to form starch citrate. The reaction involved in the In case of potato starch the intense peaks were at a paticular
preparation was shown in the Fig.1. 2θ values and in case of the starch citrate intensity of the

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peaks were decreased but it was spread over region of the Flow properties
2θ values. The XRD of the potato starch and potato starch The values of Angle of repose, Carr’s index and
citrate were found to be different and indicates that the Hausners ratio were shown in table.3. The prepared tablet
crystalinty of the starch and starch citrate were found to be blends were having good flow properties. The values of the
different. The crystalinty structure was increased in case of angle of repose, carr’s index, hausner ratio were within the
the potato starch citrate. The change in the crystalinity may limits.
be due to the addition of the citric acid to the starch.
Fourier transform infrared
Drug content in solid dispersions The FTIR spectra of the mefenamic acid, starch
Drug content in solid dispersions were determined citrate and solid dispersions were shown in the Fig.6.
by using UV. Drug content in solid dispersions was found to
be 99.473%.

Table 1. Formulae Mefenamic acid tablets formulated employing Starch citrate by Wet Granulation and Direct
Compression Methods
Formulation
Ingredient (mg/Tablet)
MF1 MF2 MF3 MF4
Mefenamic acid 100 100 100 -
Starch citrate - - 250 -
Mefenamic acid – starch citrate solid dispersion (1:2) - - - 300
MCC 256 - - -
Lactose - 256 6 56
Crospovidone 20 20 20 20
Acacia 8 8 8 8
Talc 8 8 8 8
Magnesium stearate 8 8 8 8
Total weight of tablet (mg) 400 400 400 400

Fig 1. Chemical reaction involved in the preparation of the starch citrate

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Fig.2. Microscopic images of (A) Starch and (B) Starch citrate

Table.2. Physical properties of the Potato Starch citrate prepared


S.NO Property Result
1 Solubility Insoluble in all aqueous and organic solvents
2 pH(1% w/v aqueous dispersion) 4.78
3 Melting point Charred at 2220C
4 Viscosity (1% w/v aqueous dispersion) 0.9906 cps
5 Swelling index 1100
No gelling and the swollen particles of starch citrate separated from
6 Gelling property
water. Where as in the case of starch, it was gelatinized and formed gel
7 Density 0.605 g/cc
8 Angle of Repose 20.04o
9 Compressibility Index 8.33%

Fig.3. FTIR spectra of the (A) Citric acid, (B) Starch and (C) Starch citrate

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Fig.4. DSC thermograms of (A) Citric acid, (B) Starch and (C) Starch citrate

Fig.5. X-Ray Diffractograms of (A) Starch and (B) Starch citrate

Table.3. Flow properties of Solid dispersions


Formulation Angle of repose Carr’s index Hausner ratio
P1 23.14 ± 0.86 15.86 ± 0.25 1.11 ± 0.07
P2 22.49 ± 1.18 13.25 ± 0.41 1.13 ± 0.01
P3 21.59 ± 0.72 14.5 ± 0.10 1.13 ± 0.01
P4 21.02 ± 0.68 15.06 ± 0.73 1.15 ± 0.03

Fig.6. FTIR spectra of the (A) Starch citrate (B) Mefenamic acid, (C) Mefenamic acid+MCC (D) Mefenamic acid+starch citrate
and (E) Mefenamic acid+lactose

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Fig.7. Dissolution profile of Mefenamic acid tablets

Table.4. Characteristics of prepared Mefenamic acid tablets


Drug
Weight Hardness Disintegration
Code content Thickness (mm) Friability (%)
variation(mg) (kg/cm2) Time (Min)
(%w/w)
MPF1 98.05263 400.55 ±0.792 5.12 ± 0.025 0.465 ± 0.03 7 1.46± 0.41
MPF2 99.23684 400.4 ± 0.744 5.16 ± 0.046 0.494 ± 0.02 7 1.34 ± 0.60
MPF3 99.00000 401.21 ± 0.10 5.12 ± 0.054 0.475 ± 0.10 8 0.26± 0.15
MPF4 99.71053 402.21 ±0.948 5.14 ± 0.049 0.504 ± 0.05 8 0.29± 0.80

Table.5. Dissolution parameters of Mefenamic acid tablets


Parameters Q30a Q45a DE30b DE45b MDRc IDRc t50% (min)c
Commercial tablets 41.210 51.157 27.414 27.670 2.591 4.310 43.26
MF1 28.657 37.184 17.490 19.089 1.543 2.373 >45
MF2 21.221 29.131 13.256 14.466 1.222 1.927 >45
MF3
72.947 92.605 44.210 48.039 3.994 6.3 15.17
MF4 81.236 98.526 54.195 54.197 5.123 8.572 8.35
a Q: percent drug released at 30, and 45 min.,b DE: Dissolution efficiency at 30 and 45 min. c MDR, IDR and t50% (min): mean
dissolution time, mean dissolution rate, initial dissolution rate, relative dissolution rate and time taken to release 50% of the
drug and respectively.

The mefenamic acid was shown significant peaks ranged from 400.21 to 402.21 mg. The weight variations for
at 3307.40 cm-1 indicates N-H stretching, intense bands at all the formulated tablets were within the Pharmacopoeial
1570.04 cm-1 indicates N-H bending, 1645.18 cm-1 indicates limits. The thickness of tablets ranged between 5.12mm to
C=O stretching, 746 cm-1 indicates aromatic stretching. 5.16 mm for Mefenamic acid tablets. All the formulated
These characteristic peaks were also observed in FTIR tablets showed uniform thickness. The percentage friability
spectrum of solid dispersions formulation suggesting that of all the formulations are within the limit (Limit: NMT
there were no interactions between the drug and polymer. 1.0%) and has required mechanical strength. The hardness
of the various tablet formulation are uniform with 7-8
Evaluation of tablets kg/cm2 (n=3), which is required to maintain the mechanical
Tablets of four different batches each containing strength. Drug content was found to be in the range of
100 mg of mefenamic acid were prepared by wet 98.05-99.71% and the values of drug content were reported
granulation and direct compression method. Results of the in the table.4.
FTIR study were suggesting that there was no drug The in-vitro disintegration time of various
interactions were observed. The prepared tablet blend was Mefenamic acid tablets are depicted in the table.4. The
evaluated for flow properties and these results were disintegration time was 0.26 ± 0.15-1.46± 0.41 min. Tablets
suggesting that prepared tablet blend was having good flow prepared by using starch citrate were disintegrated quickly
properties and the values of angle of repose, carr ’s index, compared to tablets prepared lactose and microcrystalline
hausner’s ratio were shown in table.3. The Average weight

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cellulose. The swelling property of starch citrate aided in CONCLUSION


disintegration of the tablet. In the present study the starch citrate was prepared
The in vitro dissolution study performed in pH 7.4 by reacting the citric acid with starch at elevated
phosphate buffer and shows maximum release of drug at the temperature. Prepared starch citrate was found to be
end of 45 min. MF4 formulation was shown maximum insoluble in water, organic solvents, acidic and alkaline pH.
amount drug release at 45min. The dissolution efficiency of Starch citrate was exhibited good flow properties. Starch
tablets suggests that increased solubility and dissolution rate citrate was characterized by FTIR, DSC and XRD and these
of Mefenamic acid. The initial dissolution rate was results were suggesting that structure of starch had been
enhanced up to 8.572. At the end of 45 min commercial modified. Chemically modified starch had good swelling
tablets showed a maximum release of 51.15% of the drug property without pasting when heated in water was consider
where as tablets of MP1, MP2, MP4 and MP5 showed to be promising excipient for tablet formulation and also as
37.18%, 29.13%, 92.6 and 98.52% respectively. P4 a carrier for solid dispersions for enhancing the dissolution
formulation was shown 97.342% drug release at 45min. rate of poorly water soluble drugs. Results of the FTIR were
DE45 of commercial tablets, MP1, MP2, MP3 and MP4 was revealed that there were no interactions between the drug
found in the order of the 27.67, 19.08, 14.46, 48.03 and and polymer. Dissolution parameters of mefenamic acid
54.19. Mean dissolution rate was improved up to 5.123. were improved in tablets prepared by using starch citrate as
Time taken by the MP4 formulation to release 50% of drug direct compressible disintegant, starch citrate-mefenamic
was found to be 8.35 minutes. The dissolution parameters acid solid dispersions when compared to tablets prepared by
(DE, MDR, IDR, t50%) of tablets suggest that increased using microcrystalline cellulose and lactose. It was
dissolution rate of Mefenamic acid from the tablets prepared concluded that starch citrate is a promising excipient for
by starch citrate as a direct compressible vehicle and as a tablet formulation and also as a carrier for solid dispersions
disintegrant, solid dispersions when compared to tablets for enhancing the dissolution rate of poorly water soluble
prepared by using microcrystalline cellulose and lactose. drugs.

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