FORMULATION AND EVALUATION OF FAST DISSOLVING TABLETS OF CANDESARTAN CILEXETIL USING NATURAL AND SYNTHETIC SUPERDISINTEGRANTS
Basawaraj S.Patil1*, N.G.Raghavendra Rao2
1Research scholar, Singhania University, Pacheri Bari, Dist. Jhunjhunu - Rajasthan, India 2Department of Pharmaceutics, Luqman College of Pharmacy, Gulbarga – Karnataka, India
Keywords: Candesartan cilexetil, Fast dissolving tablets, Plantago ovata mucilage, Superdisintegrants.
Abstract

In the present work attempts were made to prepare fast dissolving tablets (FDT) of candesartan cilexetil by direct compression method with a view to enhance patient compliance. The synthetic and natural superdisintegrants used in this study were croscarmellose sodium, and plantago ovata mucilage. Tablets having superdisintegrant at different concentration (2.5, 5, 7.5 and 10 mg) level were prepared. The prepared batches of tablets were evaluated for uniformity of weight, thickness, hardness, friability, drug content, wetting time, in vitro dispersion time and in vitro dissolution study. Swelling index was also investigated with an aim to compare the swelling property of plantago ovata mucilage with synthetic superdisintegrant. Compare to croscarmellose sodium, plantago ovata mucilage showed the highest swelling index. Hence, the present work revealed that this natural superdisintegrant, plantago ovata mucilage showed better disintegrating property than the most widely used synthetic superdisintegrants in the formulation of fast dissolving tablets.

Article Information

Identifiers and Pagination:
Year:2011
Volume:3
First Page:250
Last Page:261
Publisher Id:JAppPharm (2011 ). 3. 250-261
Article History:
Received:March 9, 2011
Accepted:June 11, 2011
Collection year:2011
First Published:July 5, 2011

INTRODUCTION
Candesartan cilexetil is chemically 2-Ethoxy-3-[21-(1H-tetrazol-5-yl) biphenyl-4-
ylmethyl] -3Hbenzoimidazole- 4-carboxylic acid 1- cyclohexyloxycarbonyloxy ethyl ester [1].
Candesartan cilexetil is a prodrug of candesartan – a compound that inhibits binding of
angiotensin II to the AT1 – receptor. Candesartan cilexetil is hydrolyzed to candesartan during
absorption from the gastrointestinal tract [2]. It is mainly used in the treatment of hypertension.
The typical dose of candesartan cilexetil is 16 mg per day in patients who are not volume
depleted. It may be given once or twice daily with total daily doses ranging from 8 mg to 32 mg
[3]. Tablet formulation containing 4 mg and 8 mg candesartan cilexetil are available in market.
Now a day fast dissolving tablets are gaining more importance in the market. Currently these
tablets are available in the market for treating many disease conditions. More is concerned on
hypertension, migraine, dysphasia, nausea and vomiting, Parkinson’s disease, schizophrenia,
pediatric emergency. [4-10]. These conditions are those, which require the drug to be formulated
as fast dissolving tablets. Some patient prefers fast dissolving tablets to conventional tablets best
of ease of administration, swallowing, pleasant taste and availability in several flavors [11]. The
paediatric and geriatric patients are of particular concern. To overcome this, dispersible
tablets[12] and fast-disintegrating tablets[13] have been developed. Most commonly used
methods to prepare these tablets are; freeze-drying/lyophilization [14] tablet molding[15] and
direct-compression methods[16]. Lyophilized tablets show a very porous structure, which causes
quick penetration of saliva in to the pores when placed in oral cavity[17]. The main
disadvantages of tablets produced are, in addition to the cost intensive production process, a lack
of physical resistance in standard blister packs and their limited ability to incorporate higher
concentrations of active drug. Molded tablets dissolve completely and rapidly. However, lack of
strength and taste masking are of great concern [18]. Main advantages of direct compression are
low manufacturing cost and high mechanical integrity of the tablets [19].
In the present study, an attempt was made to develop fast dissolving tablets of candesartan
cilexetil using natural and synthetic superdisintegrants to improve its bioavailability.
MATERIALS AND METHODS
Candesartan cilexetil was gift sample from Hetero Labs. Ltd. Medak district. (Andhra Pradesh,
India). Seeds of plantago ovata were purchased from local market of Gulbarga, Karnataka, India.
Croscarmellose sodium, mannitol, microcrystalline cellulose talc, magnesium stearate, and all
the other chemicals used were of pharmaceutical grade.
Isolation of Mucilage
The seeds of plantago ovate were soaked in distilled water for 48 h and then boiled for few
minutes so that mucilage was completely released into water (Washi, 1985). The material
collected was squeezed through muslin cloth for filtering and separating out the marc. Then, an
equal volume of acetone was added to the filterate so as to precipitate the mucilage. The
separated mucilage was dried (in oven at temperature less than 600 C), powdered, sieved (# 80)
and stored in a desicator until use.
Swelling index
Swelling index (B.P. Vol. II, 1988) is the volume in milliliters that is occupied by 1 gm of drug
or any adhering mucilage after it has swollen in an aqueous liquid for 4 h. The method of
studying swelling index for plantago ovata, croscarmellose sodium were carried out as per BP
specifications. Swelling index was calculated from mean readings of three determinations (Table
1).
Table 1: Swelling index for superdisintegrants
Preparation of fast dissolving tablets of candesartan cilexetil
Fast dissolving tablets of candesartan cilexetil were prepared by direct compression. All the
ingredients (except granular directly compressible excipients) were passed through # 60 mesh
separately. Then the ingredients were weighed and mixed in geometrical order and compressed
into tablets of 100 mg using 6 mm round punches on 10-station rotary tablet machine (Rimek
Mini Press-1). A batch of 50 tablets of each formulation was prepared for all the designed
formulations. Different formulations compositions are given in Table 2.
Evaluation of powder blends [20-23]
Bulk density
Apparent bulk density (b) was determined by placing pre-sieved drug excipients blend into a
graduated cylinder and measuring the volume (Vb) and weight (M) “as it is”.
b = M/Vb
Tapped density
The measuring cylinder containing a known mass of blend was tapped for a fixed number of
taps. The minimum volume (Vt) occupied in the cylinder and the weight (M) of the blend was
measured. The tapped density (t) was calculated using following formula.
t = M/ Vt
Angle of repose
Angle of repose () was determined using funnel method. The blend was poured through a
funnel that can be raised vertically until a maximum cone height (h) was obtained. The radius of
the heap (r) was measured and angle of repose was calculated.
 = tan-1 h/r
Compressibility index
The simplest way of measurement of free flow property of powder is compressibility, an
indication of the ease with which a material can be induced to flow is given by %
compressibility, which is calculated as follows:
C = (t – b) / t x 100
t - Tapped density, b - Untapped bulk density
Hausner’s ratio
Hausner’s ratio is an index of ease of powder flow; it is calculated by following formula.
Hausner’s ratio = t /b
t - Tapped density, b -Untapped bulk density
Evaluation of Sertraline fast dispersible tablets [24-26]
Weight variation test
Weight variation test was done by weighing 20 tablets individually, by using Shimadzu digital
balance (1mg sensitive). Calculating the average weight and comparing the individual tablet
weight to the average weight.
Tablet thickness
The thickness was measured by placing tablet between two arms of the Varnier calipers. 5 tablets
were taken and their thickness was measured.
Tablet hardness
The tablet hardness, which is the force required to break a tablet in a diametric compression
force. The hardness tester used in the study was Monsanto hardness tester, which applies force to
the tablet diametrically with the help of an inbuilt spring.
Tablet friability
The friability of the tablets was measured in a Roche friabilator (Camp-bell Electronics,
Mumbai). Tablets of a known weight (Wo) or a sample of 20 tablets are dedusted in a drum for a
fixed time (100 revolutions) and weighed (W) again. Percentage friability was calculated from
the loss in weight as given in equation as below. The weight loss should not be more than 1 %.
Determination was made in triplicate.
% Friability = 100 (Wo -W) / Wo
Drug Content Uniformity
For the content uniformity test, ten tablets were weighed and pulverized to a fine powder,
a quantity of powder equivalent to 4 mg of candesartan cilexetil was extracted into 6.8 pH buffer
solution (containing 0.1% polysorbate) and liquid was filtered (0.22 mm membrane filter disc
(Millipore Corporation). The candesartan cilexetil content was determined by measuring the
absorbance at 255 nm (PG instrument UV-Visible spectrophotometer T80 model) after
appropriate dilution with 6.8 pH buffer solution. The drug content was determined using
standard calibration curve. The mean percent drug content was calculated as an average of three
determinations.
In vitro dispersion time
Tablet was added to 10 ml of phosphate buffer solution (pH 6.8) at 37 ± 0.50C. Time required for
complete dispersion of a tablet was measured. (Fig.1)
Wetting Time and Water Absorption Ratio (R)27
Twice folded tissue paper was placed in a petri dish having an internal diameter of 5 cm
containing 6 ml of water. A tablet was carefully placed on the surface of the tissue paper in the
Petri dish. The time required for water to reach the upper surface of the tablet and to completely
wet it was noted as the wetting time. Water absorption ratio (R) was then determined according
to the following equation:
R = 100 x (wa – wb)/ wb
Where wb and wa were tablet weights before and after water absorption, respectively.
In vitro dissolution study
The release rate of candesartan cilexetil from fast dissolving tablets was determined using United
State Pharmacopoeia (USP) XXIV dissolution testing apparatus II (paddle method). The
dissolution test was performed using 900 ml of phosphate buffer pH 6.8 as a dissolution medium,
(containing 0.1% polysorbate 20) at 37 ± 0.50C and 50 rpm. A sample (5 ml) of the solution was
withdrawn from the dissolution apparatus at different time interval (minutes). The samples were
filtered through a 0.45 m membrane filter. Absorbance of these solutions was measured at 255
nm using a PG instrument UV-Visible spectrophotometer T80 model. Cumulative percentage of
drug release was calculated using an equation obtained from a standard curve.
FTIR studies
The Fourier-transform infrared spectra of candesartan cilexetil and mixture candesartan cilexetil
with other excipients were obtained by using FTIR spectroscopy – 5300 (JASCO Japan).
Samples were prepared by KBr pressed pellet technique. The scanning range was 400 -4600 cm-1
and the resolution was 4 cm-1. The spectra are shown in Fig. 2.
RESULTS AND DISCUSSION
FTIR studies revealed that there was no physico-chemical interaction between Candesartan
cilexetil and other excipients. Swelling index of plantago ovata mucilage was more than that of
synthetic superdisintegrant croscarmellose sodium. The values of pre-compression parameters
evaluated were within prescribed limits and indicated good free flowing properties are given in
Table 3. The data obtained from post-compression parameters in all the formulations, friability is
less than 1%, indicated that tablets had a good mechanical resistance. Drug content was found to
be in the range of 98.48 to 100.27 %, which is within acceptable limits. Hardness of the tablets
was found to be in the range of 3.1 to 3.8 kg/cm2. In vitro dispersion times were found to be in
the range of 20 to 62 sec. The water absorption ratio and wetting time, which are important
criteria for understanding the capacity of disintegrants to swell in presence of little amount of
water, were found to be in the range of 49 to 83 % and 21 to 59 sec respectively are given in
Table 4 & 5. The dissolution profiles of formulations are shown in Fig 3 & 4. The dissolution
profiles of all formulations are shows the release of drug 99 % within 9 min. The formulations
CPO4and CCS4 shows drug release within 4 & 5 min. Compare to croscarmellose sodium
formulations, plantago ovata formulations shows faster release of drug, this is due to more
swelling property of plantago ovata mucilage. In case of formulation CPO4, the 50% and 90% of
drug release was found within 0.39 and 1.54 min is shown in Fig. 5.
CONCLUSION
The present work revealed that the natural superdisintegrant, plantago ovata mucilage showed
better disintegrating and dissolution property than the most widely used synthetic
superdisintegrants in the formulation of fast dissolving tablets
ACKNOWLEDGEMENTS
The authors are thankful to Hetero Labs. Ltd. Medak district. (AP - India) for providing
Candesartan cilexetil drug sample.
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Welcome to the research group of Prof. Dr. Cornelia M. Keck in Marburg. Cornelia M. Keck is a pharmacist and obtained her PhD in 2006 from the Freie Universität (FU) in Berlin. In 2009 she was appointed as Adjunct Professor for Pharmaceutical and Nutritional Nanotechnology at the University Putra Malaysia (UPM) and in 2011 she obtained her Venia legendi (Habilitation) at the Freie Universität Berlin and was appointed as a Professor for Pharmacology and Pharmaceutics at the University of Applied Sciences Kaiserslautern. Since 2016 she is Professor of Pharmaceutics and Biopharmaceutics at the Philipps-Universität Marburg. Her field of research is the development and characterization of innovative nanocarriers for improved delivery of poorly soluble actives for healthcare and cosmetics. Prof. Keck is executive board member of the German Association of Nanotechnology (Deutscher Verband Nanotechnologie), Vize-chairman of the unit „Dermocosmetics“ at the German Society of Dermopharmacy, active member in many pharmaceutical societies and member of the BfR Committee for Cosmetics at the Federal Institute for Risk Assessment (BfR).

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