Usmani et al

Tropical Journal of Pharmaceutical Research January 2015; 14 (1): 1-6

ISSN: 1596-5996 (print); 1596-9827 (electronic)
Pharmacotherapy Group, Faculty of Pharmacy, University of Benin, Benin City, 300001 Nigeria.
All rights reserved.

Available online at http://www.tjpr.org

http://dx.doi.org/10.4314/tjpr.v14i1.1
Original Research Article

Development and Evaluation of Orally Disintegrating

Tablets of Montelukast Sodium by Direct Compression
Method
Muhammad Talha Usmani1, Muhammad Harris Shoaib1, Muhammad Iqbal
1
Nasiri *, Rabia Ismail Yousuf1, Kamran Zaheer2 and Kamran 2Ahmed2
1
Department of Pharmaceutics, Faculty of Pharmacy, University of Karachi, Karachi, Pakistan, Department of Pharmaceutics,
Faculty of Pharmacy, Hamdard University, Karachi, Pakistan

*For correspondence: Email: iqbalnasiri@hotmail.com; Tel: +923343377643

Received: 1 April 2014 Revised accepted: 27 November 2014

Abstract
Purpose: To design an orally disintegrating montelukast sodium tablet (ODT) that disintegrates in the
oral cavity leaving an easy-to-swallow residue especially for pediatric and elderly patients who have
difficulty swallowing tablets.
Methods: Two different formulations of montelukast sodium (5 mg) orally disintegrating tablets were
designed and manufactured by direct compression method, using microcrystalline (Avicel PH-102),
mannitol, sodium bicarbonate, crospovidone and magnesium stearate as key excipients, and with
cherry flavor and aspartame as flavor and sweetener, respectively. These formulations were then
evaluated using pharmacopoeial and non-pharmacopoeial physical and chemical tests. Dissolution and
assay tests were performed using USP apparatus II and ultraviolet (UV) spectrophotometry,
respectively. Formulations with better results were further subjected for optimization study using central
composite design method.
Results: The results of prototype formulation batch (Trial-02) and the finest optimization formulation
batch (FOB-01) reflected the successful development of new formulation of orally disintegrating
montelukast sodium 5 mg tablet by direct compression technique. The value of similarity factor (f2 > 50),
indicating that both formulations have similar drug release profiles. The formulations were further
evaluated for three and six months under accelerated conditions to ascertain their stability.
Conclusion: The results obtained demonstrate the suitability of the formulation as an ODT for
convenient delivery of montelukast sodium for asthmatic patients. However, clinical studies are required
to confirm this.

Keywords: Orally disintegrating tablets, Asthma, Disintegration, Dissolution, Montelukast sodium

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INTRODUCTION procedure by which tablets are manufactured

directly from the powder blends of active
Historically, the oral route of drug administration pharmaceutical ingredient/s and appropriate
has been used most preferably for both excipients [2].
conventional as well as for novel drug delivery
because of the ease of administration and Orally disintegrating tablets (ODTs) offer several
widespread acceptance by patients [1]. The term advantages over the conventional oral dosage
direct compression is employed to describe the forms particularly in terms of patient compliance

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 Usmani et al

i.e. convenience and ease of use [3]. One flavor (Northville Laboratories), aspartame
negative aspect of solid oral dosage forms is (NutraSweet Company), magnesium stearate
dysphagia (difficulty in swallowing) and chewing (Coin Chemical Industries Co. Ltd). All other
in some patients particularly in geriatric and chemicals used were of analytical grade.
paediatric patients [4]. Orally disintegrating
tablets (ODT) are well established dosage forms Experimental design
that disintegrate in the oral cavity leaving an
easy-to-swallow residue. ODTs disintegrate Factorial design was used to systematically
rapidly in saliva without the need of water, within investigate the product variables that influence
few seconds to minute [5]. Montelukast sodium is product quality. A two level factorial design study
was planned using the selected dependent
a selective, orally active leukotriene receptor
variables and effect on the dependent variable
antagonist that inhibits the cysteinyl leukotriene
was measured. Based on the relationship
CysLT1 receptor. CysLTs receptors have been between the cause and effect, optimum formula
correlated with the pathophysiology of asthma was determined and pilot batches have been
and allergic rhinitis [6]. It is rapidly absorbed after manufactured using the optimized formulation.
administration reaching peak plasma The levels composed of one at the higher side
concentration (Cmax) in 3 to 4 h with a mean and other at the lower side of the standard /
bioavailability of 64 % following a 10 mg oral existent value of each independent variable and
administration. For the 5 mg chewable tablet, the the data was analyzed using Design-Expert
mean Cmax is achieved in 2 to 2.5 h with a mean software (DX9) version 9 (Stat-Ease, Inc. USA)
bioavailability of 73 % fasting versus 63 % with and the analysis are shown in Table 1. Since we
the standard meal. More than 99 % is bound to have selected composite points of the fractional
plasma proteins with minimal distribution across composite design therefore eight experimental
the blood-brain barrier. Metabolism occurs via trial batches were manufactured containing two
liver and excretion occurs almost exclusively in trials for each independent variable.
bile with a half-life from 2.7 to 5.5 h in healthy Formulations of the proposed trials and
adults [7]. Formulation Optimization Batches (FOB) are
given in Table 3.
The objective of the present study was to
develop a formulation of montelukast sodium Preparation of tablets
orally disintegrating tablets by direct compression
process. For the optimization of the formulation, For both Trial-01 and Trial-02 batches, all the
ingredients were weighed individually and sifted
central composite design was used and
manually through mesh # 40 separately.
statistical evaluation of the formulation using
Thereafter, montelukast sodium, mannitol or
three sigma quality control charts was also
sodium bicarbonates (mannitol in trial-01 and
performed.
sodium bicarbonates in trial-02), microcrystalline
cellulose and crospovidone were mixed in a poly
EXPERIMENTAL bag for 5 min and then cherry flavor and
aspartame were added to the blend and mixed
Materials well. Magnesium stearate was finally added as
lubricant and then mixed for further 5 min. The
The materials used in the formulations with their weight of the tablet was determined as 150 mg
sources/manufacturer of ingredients are as and the tablets were compressed (Manesty D3B,
follows; montelukast sodium (Enaltec Labs (Pvt) England) using a punch and die set to produce
Ltd), mannitol (Zhongbao Chemical Corporation square shape tablets with 6.42 mm length, 6.42
Ltd), sodium bicarbonate (Brunner Mond mm width and 3.77 mm thickness dimensions.
Limited), microcrystalline cellulose (Avicel PH Each tablet contained 5 mg of montelukast
102) (Gujrat Microwax Private Limited), sodium (Table 2). Prior to compression, the
crospovidone (ISP Global Technologies ), cherry

Table 1: Factors (independent variables) and factor levels used in factorial composite design

Value in approved trial batch

Levels selected for optimization
Independent variable (factor level used)
Tablet weight 150 mg 120 170 mg
Crospovidone 4.00 % 2.00 - 6.00 %
Sodium bicarbonate 10.67 % 6.67 14.67 %

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 Usmani et al

granules were evaluated for several tests such Hardness

as angle of repose, compressibility index and
hausners ratio. Hardness of 20 tablets was determined
individually, using Hardness tester (Pharma test
Formulation optimization batches (FOB) Germany) and data were statistically analyzed
using control chart.
Same procedure followed for all formulation
optimization batches (FOB) except, mannitol was Friability
replaced by sodium bicarbonate. The weight of
tablet was calculated as 150 mg except for FOB- Friability of 20 tablets was determined using
01, 120 mg and FOB-02, 170 mg (Table 3). All Friabilator (Electrolab India and Mettler Toledo).
the other parameters were same as used for Percent friability was calculated by using
trial-01 and trial-02 batches as shown in Table 2. equation 1.

Evaluation of tablets F (%) = [(W1 W2)/W1] 100 .(1)

Thickness where, F = friability, W1 = Weight of the tablet

before testing and W2 = Weight of the tablet after
The thickness of the tablets was determined testing.
using a Vernier caliper. Twenty tablets from each
batch were used, and data were statistically In vitro disintegration test
analyzed using control chart.
The in vitro disintegration test was performed on
Weight variation test each formulation using USP disintegration
apparatus (Pharma test, Germany). European
To study weight variation, 20 tablets of each Pharmacopoeial method was followed for all
formulation were weighed using an electronic formulations. Six tablets of each formulation were
balance (Mettler Toledo), and the test was tested for disintegration. Distilled water was used
performed according to the official method. as disintegration medium at 37 2 C
temperature. The time taken until no material

Table 2: Composition of prototype formulations

Ingredient
Trial-01 (mg/tab) Trial-02 (mg/tab)
Montelukast Sodium 5.20* 5.20*
Mannitol 70.000 -
Microcrystalline Cellulose 48.800 116.80
Sodium Bicarbonate - 16.00
Crospovidone 20.000 20.000
Aspartame 2.000 2.000
Cherry Flavour 2.000 2.000
Magnesium Stearate 2.000 2.000
Total 150.00 150.00

Table 3: Formulations of optimization batches

Trial-02 FOB-01 FOB-02 FOB-03 FOB-04 FOB-05 FOB-06

Ingredient
mg/tab mg/tab mg/tab mg/tab mg/tab mg/tab mg/tab
Montelukast sodium 5.20* 5.20* 5.20* 5.20* 5.20* 5.20* 5.20*
Microcrystalline cellulose 116.800 92.410 133.080 122.790 110.790 119.800 113.800
Sodium bicarbonate 16.000 12.804 18.139 10.005 22.005 16.000 16.000
Crospovidone 6.000 4.800 6.800 6.000 6.000 3.000 9.000
Aspartame 2.000 1.596 2.261 2.000 2.000 2.000 2.000
Cherry flavour 2.000 1.596 2.261 2.000 2.000 2.000 2.000
Magnesium Stearate 2.000 1.596 2.261 2.000 2.000 2.000 2.000
Total weight (mg) 150.00 120.00 170.00 150.00 150.00 150.00 150.00

Trop J Pharm Res, January 2015; 14(1): 3

 Usmani et al

from any of the tablets was left on the mesh was period of 3 and 6 months for the stability
recorded in seconds. indicating parameters such as appearance,
weight variation, hardness, disintegration,
Assay of montelukast sodium dissolution and assay.

Assay of drug was carried out using average Statistical analysis

weight of the crushed tablets equivalent to the
weight of single tablet into 50 ml volumetric flask. The cumulative percentage of drug Montelukast
Methanol (25 ml) was added,, sonicated for 2 sodium release from the dosage form (n =6) in
min and made up the volume with same solvent the dissolution medium was tested for a
and mixed thoroughly for 15 min. UV absorbance statistical significance by using of One-way
of the filtered solution was measured using UV- ANOVA test between the two values. The level of
Visible spectrophotometer [UV 2450, Shimadzu significance was set at p < 0.05.
Corporation, Japan] at 285 nm (max). Standard
working solution was prepared by weighing RESULTS
accurately 25 mg of montelukast sodium into a
100 ml volumetric flask following the similar Physicochemical properties of compressed
procedure for sample solution and dilution ODTs
procedure. From the absorbance of the sample
solution and standard solution, the amount of
All the formulations were evaluated for weight
drug in the percentage assay of ODTs was
variation, hardness, friability, thickness,
calculated.
disintegration and assay and their results are
In vitro dissolution studies shown in Table 4. From the evaluation
parameters, it was observed that weight and
In vitro dissolution studies were performed for the thickness of all batches complied with the
tablets (n = 6) using USP dissolution apparatus II desired specification except FOB-02 for which
(paddle type), at 50 rpm, thermostatically thickness was high but was within limits of 5 %.
maintained at temperature 37 0.5 oC, with Hardness of all formulations was between 8.45
dissolution medium of 500 ml having 0.2 % of and 15.85 kg/cm2 and this was found satisfactory
sodium lauryl sulphate in it. Dissolution study and within desired specification. The friability test
was carried out for duration of 30 min with results of all formulations were < 1 % and it was
sampling interval of 5 minutes, 10 minutes, 20 also found to be within the limits specified in the
minutes, and 30 minutes. The absorbance of B.P.
both test solution and standard solution at 285
nm taking 0.2 % Sodium Lauryl Sulphate as Assay determination was done using UV
blank. spectrophotometer for the detection of
montelukast sodium at a wavelength of 285 nm.
Stability studies On the basis of pharmaceutical assay results of
montelukast in all formulations was > 98 %
The product was packed in Alu/Alu blister and (Table 4). It was concluded that concentrations of
was stored according to storage condition active ingredient in tablets of all three
recommended for accelerated conditions in ICH formulations (FOB-01, FOB-03, and FOB-06) of
guidelines. Stability condition used were,
montelukast orally disintegrating tablet was found
temperature 40 2 C and relative humidity 75
satisfactory.
5 % RH. Accelerated study was conducted for a

Table 4: Physicochemical characteristics of ODT tablets

Batch Thickness** Hardness** Weight Variation Friability** Disintegration Assay*

2
code (mm) (Kg/cm ) test** (mg) (%) test*** (s) (%)
Trial-01 3.79 0.03 14.54 1.02 150.45 1.8 0.06 0.02 401.4 101.89 0.02
Trial-01 3.78 0.02 9.77 1.24 149.85 2.1 0.11 0.03 101.6 100.58 0.03
FOB-01 3.07 0.01 9.35 0.17 120.55 1.3 0.04 0.02 082.6 99.63 0.02
FOB-02 3.79 0.01 15.85 0.71 169.90 2.7 0.17 0.03 352.2 98.76 0.02
FOB-03 3.74 0.03 10.28 0.99 150.10 0.8 0.08 0.01 221.4 99.26 0.13
FOB-04 3.75 0 .02 8.79 0.50 150.20 2.1 0.12 0.03 051.3 98.16 0.03
FOB-05 3.77 0.02 8.45 0.54 150.25 1.0 0.06 0.02 141.3 99.25 0.04
FOB-06 3.74 0.02 8.94 0.59 150.25 1.7 0.05 0.05 101.6 99.61 0.15
*All values are expressed as mean SD, n = 3; ** All values are expressed as mean SD, n = 20; ***All values
are expressed as mean SD, n = 6

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 Usmani et al

In vitro disintegration test DISCUSSION

The in vitro disintegration time for all the Orally disintegrating tablets (ODTs) offer several
compressed tablets was determined and results advantages over the conventional oral dosage
of all formulations are given in Table 4. forms particularly in terms of patient compliance
i.e. convenience and ease of use. Over the past
The time for disintegration of orodispersible decade, considerable progresses in the
tablets (orally disintegrating tablets) is generally formulation of ODTs have been accomplished in
< 1 min and the actual time that patient can academic research and industry that resulted in
experience ranges from 5 to 30 s. the rising of a large number of patents [3].

In vitro dissolutions studies Any dosage form that disintegrates or dissolves

rapidly offer more compliance for pediatric and
geriatric patients having difficulty in swallowing,
The time points were selected based on the FDA
and in conditions where potable water is not
recommendation for most orally disintegrating readily available. For such kind of formulations,
tablets. In vitro dissolution studies showed that the minute quantity of fluid such as saliva is
more than 50 % of the drug was released from all typically enough for quick disintegration of tablet
the formulations within 5 min. From in vitro in mouth. This helps the drug to be readily
dissolution data, it was observed that an average available for dissolution and subsequent
of more than 75 % of montelukast, released in absorption into the blood through the blood
the dissolution medium from all the formulations vessels of either the oral cavity or from the blood
within 15 min indicates that the tablet complies vessels of the stomach or intestine upon being
as per EP specifications, that is, not less than 70 ingested [8]. Direct compression is a major
% in 30 min shown in Figure 1. This assures manufacturing process employed in
quick delivery of active ingredient for systemic pharmaceutical technology. With this process,
absorption. granulating the powder mass before tableting is
not required which makes it a very efficient
process with no complex unit operation involved.
In order to describe a new excipent, the research
on its physicochemical properties like flowability,
physical form (crystallinity) and water content is
considered crucial as these directly effects the
properties of final dosage form [9].

The aim of the research study was to design and

develop a new formulation of orally disintegrating
montelukast 5 mg tablet by adopting the
approach of using conventional process of direct
compression, and by choosing the conventional
excipients rather than any novel one so that the
Time (minutes) final dosage form is manufactured in much
simpler and cost effective manner. This will
Figure 1: Cumulative drug release profile of all facilitate the availability of economical and
developed batches (Note: Trail-02 = FOB-01= , patient compliant product for efficient
FOB-02 = , FOB-03 = , FOB-04 = *, FOB-05 = , pharmaceutical therapy. In present study, all of
FOB-06 = ) (n = 6) the required characteristics of quality product
were considered in order to ensure that designed
Stability product must meet the expectation of official
compendia, pharmaceutical manufacturers and
The compressed tablets were stored in an customers in terms of identity, efficacy and cost
aluminum blister packs in a chamber controlled effectiveness.
at 40 2 oC and relative humidity 75 5 % for
three and six months, and then the content of Initially two formulations were proposed for
product development. Based upon the physical
montelukast was determined along with its
and chemical characteristics of the product, it
dissolution as per ICH guidelines. All parameters
was concluded that Trial-02 is more appropriate
found satisfactory which concluded that active
as it takes less time to disintegrate than Trial-01
ingredient is stable in the formulation. because quick disintegration is the core objective
of ODTs. Based on the obtained results,

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 Usmani et al

formulation optimization activity was planned for ACKNOWLEDGEMENT

Trial-02, taking theoretical compression weight,
level of sodium bicarbonate and level of The authors wish to express their thanks to Getz
crospovidone as independent variable while Pharma (Pvt) Ltd, Pakistan for providing, free of
friability, hardness and dissolution as their charge, the samples used in this study. The
response (dependent variable). The results authors acknowledge Department of
obtained from the study were statistically Pharmaceutics, Faculty of Pharmacy, University
analyzed and different evaluation approaches of Karachi for providing facilities for this work.
were made in order to obtain quality product at
minimum cost and time period. Afterwards the
new formulation was subjected for accelerated
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