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60 | P a g e International Standard Serial Number (ISSN): 2319-8141
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International Journal of Universal Pharmacy and Bio Sciences 4(5): September-October 2015
INTERNATIONAL JOURNAL OF UNIVERSAL
PHARMACY AND BIO SCIENCES IMPACT FACTOR 2.093***
ICV 5.13***
Pharmaceutical Sciences RESEARCH ARTICLE …………!!!
FORMULATION AND EVALUATION OF ORALLY DISINTEGRATING
TABLETS OF CETIRIZINE DIHYDROCHLORIDE
ManjulaTalluri1,M.DineshChandra
2, Shiva G
*3
1, 2, 3 Dept. of Pharmaceutics, PES College of Pharmacy, Bangalore, Karnataka, India.
KEYWORDS:
Anti-histaminic agent,
Cetirizine dihydrocloride,
Kyron T-114 Drug Resin
Complex, Croscarmellose
sodium, Sodium starch
glycolate, Crospovidone,
In-vitro release studies,
Orally Disintegrating
Tablets.
For Correspondence:
ManjulaTalluri *
Address:
PES College of
Pharmacy, 50 Ft.Road,
Hanumanthanagar, BSK
1st Stage, Bangalore-50.
ABSTRACT The aim of this study was to prepare oral disintegrating tablet of taste
masked Cetirizine dihydrochloride by using direct compression
method. To prevent bitter taste and unacceptable odour of the
Cetrizine dihydrochloride drug, the drug was taste masked with ion
exchange resins like Kyron-T-104 and Tulsion-412. Among the two
resins, Kyron-T-104 was selected for further studies because of high
drug loading capacity, low cost, and better drug release profile. An ion
exchange resin complex was prepared by the batch technique and
various parameters; namely, resin activation, drug: resin ratio, pH,
temperature, and stirring time, and swelling time were optimized to
successfully formulate the tasteless drug resin complex (DRC). The
drug resin complex was evaluated by in-vitro evaluation.
Complexation was confirmed by FT-IR studies. Various
superdisintegrants were tried viz. croscarmellose sodium, sodium
starch glycolate and crospovidone in different concentrations and were
evaluated for pre-compression, post compression parameters and in-
vitro dissolution studies. The tablets were evaluated for weight
variation, hardness, friability, wetting time, water absorption ratio,
disintegration time (DT), and dissolution study. The F010 formulation
with 5% crospovidone showed a comparative results with that of
reference product. The stability studies were carried out for the
optimized batch for three months and it showed acceptable results.
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INTRODUCTION:
The development of oral disintegrating tablets (ODTs) has attracted increased interest among
researchers and pharmaceutical industries over the last decade. The ODTs are designed to disintegrate
or dissolve rapidly on contact with saliva without the need for water, which makes them advantageous
to conventional tablet forms. ODTs, as novel dosage forms present several characteristics to
distinguish them from more traditional dosage forms. A major advantage of the ODT formulations is
that they combine the properties of both liquid and conventional tabletformulations1,2
. They provide
the convenience of a tablet formulation yet are easy to swallow similar to a liquid formulation. ODTs
are ingested simply by placing them on the tongue, thus eliminating the need to chew the tablet,
swallow an intact tablet, or take the tablet with water. Furthermore, administration of ODTs is
beneficial to paediatric and geriatric patients or people who find swallowing difficult and for the
treatment of patients where compliance is difficult.
However, the taste masking of bitter active substances is a critical hurdle to overcome in the
development of ODTs. Several active substances leave an unpleasant taste in the oral cavity
immediately after tablet disintegration. Therefore, taste masking is of critical importance for the
formulation of an acceptable ODT. Oral administration of bitter active substances through ODT
formulations should provide an improved degree of palatability, increased patient compliance and a
concomitantly beneficial therapeutic effect. Current methods of taste masking in fast
dissolving/disintegrating tablets in some cases include sweeteners and flavours. Nevertheless, these
additives are not a sufficient means for taste masking. Fortunately, recent developments in technology
have presented viable dosage alternatives to taste mask bitter drugs. Several approaches have been
reported which implement complexation3,4
, freeze-drying5, microencapsulation
6,7, fluidized bed
coating8,9
, high shear mixing10
and supercritical fluids11,12
for taste-masking purposes. Despite the fact
that direct compression represents one of the oldest pharmaceutical techniques, it is still regularly used
in the manufacturing of pharmaceutical dosage forms8. There are only a few studies reported where
direct compression was implemented for taste masking purposes9,13,14
. For example, ibuprofen9was
successfully taste masked by using a combination of hydroxyl propyl methylcellulose and
ethylcellulose.
Cetirizine HCl (CTZ) is a second-generation histamine H1 receptor antagonist, with a rapid onset, a
long duration of activity and is used in the treatment of allergies, hay fever, angioedema and uticaria15
.
It is available over the counter as, Zyrtec, in the form of immediate release and chewable, immediate
release tablets. Recently, it was reported that Eur and Pharmaceuticals, Inc. has developed a fast
disintegrating cetirizine HCl tablet using a combination of the microcaps ® and adva Tab®
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technologies where the bitter API is microencapsulated through coacervation to produce
tastemaskedmicroparticles16
. The aim of this twofold study was to mask the taste of a model active
substance through direct compression and to incorporate the granules produced in robust ODT
formulations. A methacrylic pH-sensitive copolymer was used as masking agent. For the development
of ODTs, the effect of the amount of superdisintegrant(s) on ODT hardness, friability and
disintegration times was assessed in order to identify the optimum formulation. The use of
superdisintegrants is a well-known approach to formulate ODTs2.
MATERIALS
Cetirizine HCl (CTZ) , was gift sample from Jubilant Life Sciences Ltd, Kyron T 114 , From Corel
PharmaChem, Crospovidone , from Ashland Ltd,Croscarmellose sodium , From FMC Biopolymer Ltd
, Sodium starch glycolate , From DFE Pharm Ltd,Mannitol From Roquette Ltd) , Aspartame , From
IFF Ltd, Peppermint , From IFF Ltd, Magesium Stearate , From Ferro Industries Ltd.
COMPATIBILITY STUDY17,18,19,20
:
A compatibility study focuses on a binary mixture of drug substance and some selected excipients in a
fixed ratio with or without added moisture. The mixture is stored at an elevated temperature in capped
vials. The result of the interaction between the active drug and excipients may be determined by FT-IR
or solution colorimetry.
PROCEDURE
A. Drug and Excipients mixture shall be prepared based on the information from Physician Desk
Reference (PDR).
B. The Drugs and Excipients individually and in combination shall be subjected for accelerated study
conditions along with control samples and study at fixed intervals.
C. The recommended drug- excipients ratios for solid dosage forms are tabulated below.
D. After exposure of samples to the study conditions, the following parameters should be analyzed.
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Table No. 1 : “Recommended Drug Excipients Ratios For Compatibility Studies In Solid Dosage”
Name of
Excipient
Quantity of Drug in mg
<5 mg
5≤ 10mg
10 ≤50mg
50≤200mg
20≤ 500mg
≥500mg
Fillers &
Diluents
1:40
1:20
1:10
1:5
1:2
1:1
Disintegrants
/ Polymers
1:10
1:5
1:1
1:1
1:0.5
1:0.25
Binders
1:10 1:5 1:1 1:0.5 1:0.25 1:0.1
Lubricants
1:0.5 1:0.5 1:0.25 1:0.1 1:0.05 1:0.05
Coating
agents
1:5
1:5
1:1
1:0.5
1:0.25
1:0.1
Colours /
Sweeteners
1:0.05
1:0.05
1:0.05
1:0.05
1:0.05
1:0.05
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Table No. 2 :“Compatibility Parameters To Be Analysed” Test Parameters
Name of
drug/Excipients
Composition Details
Ratio Initial Period-15 & 30 Days
40°C/75%
RH 25°C/60%RH 2-8°C
API Cetirizine
dihydrochloride
- A A A Control
Samples
API + Ion
exchange resin
Cetirizine
dihydrochloride +
Kyron T-114
1:5 A A A Control
Samples
API + Super
disintegrant
Cetirizine
dihydrochloride + Croscarmellose
sodium
1:5 A A A Control
Samples
API + Super disintegrant
Cetirizine dihydrochloride +
Sodium starch
glycolate
1:5 A A A Control Samples
API + Super
disintegrant
Cetirizine
dihydrochloride +
Crospovidone
1:5 A A A Control
Samples
API + Diluent Cetirizine
dihydrochloride + Mannitol
1:20 A A A Control
Samples
API + Sweetener Cetirizine
dihydrochloride + Aspartame
1:5 A A A Control
Samples
API + Flavour Cetirizine dihydrochloride +
Peppermint
1:0.5 A A A Control samples
API + Lubricant Cetirizine
dihydrochloride + Magnesium
Stearate
1:0.5 A A A Control
samples
Where, A = Appearance
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DRUG CHARACTERIZATION
Solubility studies:
Determination of solubility of Cetirizine dihydrochloride in water:
The solubility studies were performed in distilled water, by adding excess amounts of drug in each
case and keeping the excess amounts of drug containing distilled water flasks on a rotary shaker for
24 hr. After 24 hr, solutions were analyzed spectrophotometrically at 231 nm, which was the
absorption maxima determined earlier and drug concentrations were calculated.
Determination of solubility of Cetirizine dihydrochloride in 0.1N HCl buffer:
The solubility studies were performed in 0.1N HCl buffer, by adding excess amounts of drug in
each case and keeping the excess amounts of drug containing HCl buffer flasks on a rotary shaker
for 24 hr. After 24 hr, solutions were analyzed spectrophotometrically at 231 nm, which was the
absorption maxima determined earlier and drug concentrations were calculated.
PREPARATION OF STANDARD CURVE IN DISTILLED WATER
Standard curve preparation was done using distilled water, as the drug is soluble in water. 100 mg
of Cetirizine dihydrochloride was accurately weighed and dissolved in distilled water to 100 ml
Solution. From this solution was further diluted to obtain concentrations in the range of 5-25 µg/ml.
The diluted were scanned with double beam UV-visible spectrophotometer from wavelength 200-
400 nm range. λ max was obtained at 231 nm. A standard curve was plotted to study the linearity of
Beer Lambert’s law.
METHODS
TASTE MASKING OF DRUG WITH ION EXCHANGE RESIN
Procedure:
Batch Method
1) Take demineralised water in separate vessel and keep it for stirring at 300C.
2) Add Kyron T-114 to it and stir for 10 minutes.
3) Add the API into the above with continuous stirring.
4) After adding the drug the pH will be 1.1 to 1.3.
5) Then adjust the pH to 5.5 with 10% KOH solution.
6) Then stir for 3 hours. After that do filtration and obtain the residue.
7) The residue is loaded on to stainless steel tray and then kept into a tray dryer for drying
process at 500c.
For obtaining maximum drug loading on to the resin different ratios of drug and ion exchange resin
were taken that is, 1:1, 1:2, 1:3,1:4.
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Table No. 3 :“List of Materials And Their Quantities For Formulations”
S.
No
Materials
Quantity Per Tablet (mg)
F 1 F2 F3 F4 F5 F6 F7 F8 F9 F10
Pre-lubricating Materials
1. Drug resin
complex
40.08 40.08 40.08 40.08 40.08 40.08 40.08 40.08 40.08 40.08
2. Croscarmellose
sodium
2.0 6.0 10.0 - - - - - - -
3. Sodium starch
glycolate
- - - 2.0 6.0 10.0 - - - -
4. Crosspovidone
- - - - - - 2.0 6.0 10.0 10.0
5. Mannitol 151.92 147.92 143.92 151.92 147.92 143.92 151.92 147.92 143.92 143.92
6. Aspartame 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0
7. Peppermint flavor 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0
Lubricating material
8.
Magnesium
stearate
2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0
Weight of the tablet 200.0 200.0 200.0 200.0 200.0 200.0 200.0 200.0 200.0 200.0
EVALUATION OF BLEND
Determination of Bulk density and Tapped density
The bulk density and tapped density were calculated using the following formulas
Bulk density = W/V0,
Tapped density = W/Vf
Where, W = weight of the powder
V0 = initial volume
Vf = final volume
Hausner’s ratio
It indicate the flow properties of the powder and is measured by the ratio of tapped density to the
bulk density.
Hausner’s ratio = Tapped density/Bulk density
Compressibility index (Carr’s indices)
Compressibility index is an important measure that can be obtained from the bulk and tapped
densities. In theory, less compressible the material the more flow able it is. A material having
values of less than 20 to 30% is defined as the free flowing material.
CI = 100(Vo – Vf)/Vo
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Where, CI = compressibility index,
Vo = initial volume,
Vf = final volume.
Angle of repose
In order to determine the flow property, the angle of repose was determined. It is the maximum
angle that can be obtained between the free standing surface of the powder heap and the horizontal
plane.
θ = tan-1 (h/r)
Where, h = height,
r = radius,
θ = angle of repose.
EVALUATION OF ORO-DISPERSIBLE TABLETS
Hardness:
Hardness generally measures the tablet crushing strength. The average hardness of all the batches
were measured and reported.
Friability19
The friabilator which is then operated for 100 revolutions. Compressed tablets that lose less than
0.1 to 0.5% of the tablet weight are considered acceptable. The percentage friability was measured
using the formula:
% F = {1-(W/Wo)} x 100
Where, % F = friability in percentage,
Wo = initial weight of tablet,
W = weight of tablets after revolutions
Disintegration time19
The test was carried out on 6 tablets using Tablet disintegration tester in distilled water at 37C ±
20C was used as a disintegration media and the time in second taken for complete disintegration of
the tablet with no palpable mass remaining in the apparatus was measured in seconds.
Weight Variation Test19
Take 20 tablets and weigh individually. Calculate average weight and compare the individual tablet
weight to the average.
% Maximum positive deviation = (WH-A/A) X 100
% Minimum negative deviation = (WL-A/A) X 100
Where, WH = highest weight in mg.
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WL = Lowest weight in mg.
A = Average weight of tablet in mg.
Wetting time20
The wetting time of the tablet can be measured using a simple procedure. Five circular tissues
papers of 10 cm diameter are placed in the petridish. 10ml of water containing amaranth, a water
soluble dye is added to petridish. A tablet is carefully placed on surface of the tissue paper. The
time required for water to reach upper surface of the tablet is noted as a wetting time. Six tablets
from each batch were taken and evaluated for the test.
Water absorption ratio20
A piece of tissue paper folded twice was placed in a small petridish containing 6 ml of water. A
tablet was put on the tissue paper an allowed to completely wet. The wetted tablet was then
weighed. Six tablets from each batch were used for this test. Water absorption ratio, R was
determined using following equation
R = 100 X (Wa-Wb/Wa)
Where, Wa = weight of tablet after water absorption.
Wb = weight of tab let before water absorption.
In-vitro dissolution studies:
In-vitro release studies were carried out using tablet dissolution test apparatus USP XXII type-2.
Dissolution of Cetirizine dihydrochloride oro-dispersible tablets was carried out in 0.1 N HCl
buffer solution. Sampling was done at regular time interval and the release pattern is studied using
UV analysis.
The various parameters related to dissolution which are evaluated in the present work are as
follows:
1) Drug release.
2) Cumulative percentage drug release.
One tablet in each dissolution flask was added and the apparatus was made to run for 45 minutes. 5
ml volume of sample was withdrawn from each flask at specified time interval of 5, 10, 15, 20, 35,
45 minutes and replaced with equivalent amount of fresh medium to maintain sink condition.
FT-IR STUDIES
This study was carried out by using infrared spectrophotometer to find out if there is any possible
chemical interaction of drug with used excipients.
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Weighed amount of drug (3 mg) and samples were mixed with 100 mg of potassium bromide (dried
at 40-500C). The mixture was taken and compressed under 10 ton pressure in a hydraulic press to
form a transparent pellet. The pellet was scanned in IR spectrophotometer.
Stability studies:
Stability of a drug has been defined as the stability of a particular formulation, in a specific
container, to remain within its physical, chemical, therapeutic and toxicological specifications
throughout its shelf life.
The purpose of the stability testing is to provide evidence on the quality of a drug substance or its
product, which varies with time under the influence of environmental factors such as temperature,
humidity and light. Recommended storage conditions, re-test periods and shelf lives are to be
established.
The International Conference on Harmonization (ICH) Guidelines titled “stability testing of New
Drug substances and products” describes the stability test requirement for drug registration
applications in the European Union, Japan and United States of America.
ICH specifies the length of study and storage conditions:
Long Term testing: 25ºC ± 2ºC / 60% RH ± 5% for 12 months
Accelerated Testing: 40ºC ± 2ºC / 75% RH ± 5% for 6 months
Stability studies were carried out at 25ºC / 60% RH, 30ºC / 65% RH & 40ºC / 75% RH for the
selected formulations for 3 months.
Method:
Accelerated stability studies was carried out to observe the effect of temperature and relative
humidity on selected formulation, by keeping it in 25ºC/60% RH, 30º C/65% RH and 40ºC/75%
RH conditions. For each condition the samples were withdrawn after 1month, 2month and 3 month
and the data was recorded. The evaluation was done with respect to physical appearance, hardness,
disintegration time and dissolution rate.
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RESULTS: FT-IR SPECTRUMS FT-IR Spectrum of cetirizine dihydrochloride
Figure 1:FT-IR Spectrum of cetirizine dihydrochloride
FT-IR Spectrum of Drug with Kyron T-114
Figure 2: FT-IR Spectrum of API with Kyron T-114
FT-IR Spectrum of Drug with Crospovidon XL 10
Figure 3: FT-IR Spectrum of Drug with Crospovidon XL 10
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FT-IR Spectrum of Drug with Mannitol
Figure 4: FT-IR spectrum of Drug with Mannitol
FT-IR Spectrum of Blend
Figure 5: FT-IR spectrum of Blend:
FT-IR STUDIES
The FTIR spectra of the pure drug (Cetirizine dihydrochloride) showed significant band at 3427,
2839, 2587, 1741 and 1600 cm-1 which indicates the presence of hydroxyl, ether stretching, tertiary
amine salt, carbonyl groups and phenyl nucleus skeletal stretching respectively which confirms the
purity of the drug (Figure 1). The FTIR of the sample was compared with the reference as shown in
Indian Pharmacopoeia, 2007.
Figure 2, 3, 4 and 5indicate FTIR of Cetirizine dihydrochloride in presence of Kyron T-114,
crospovidone, mannitol and blend respectively. It was observed that all prominent peaks of
Cetirizine dihydrochloride were present in the respective FTIR spectra. Thus, it can be concluded
that there was no interaction between the drug and the excipients selected in the study.
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IN-VITRO DISSOLUTION OF DRC IN SALIVARY pH
In-vitro dissolution of DRC on 6.8 pH Phosphate buffer:
Table No. 4 : “In-vitro Dissolution of DRC on 6.8 pH Phosphate Buffer”
S. No Time (min) % Drug Release
From DRC
1 0 0
2 5 1.2
3 10 1.8
4 15 2.1
5 20 2.2
6 30 2.2
7 45 2.3
Figure 6: In-vitro dissolution graph of DRC in 6.8 pH Phosphate buffer
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EVALUATION OF FORMULATIONS:
Evaluation of Pre compression parameters of formulations F001-F010: Table No. 5 :“Evaluation of Pre compression parameters of formulations F001 -F010”
S No Formulation
Codes
Angle of
Repose(θ)
Bulk
Density
(gm/cm3)
Tapped
Density(gm/cm3)
Compressibility
Index(%)
Hausner’s
Ratio
1 F001 28 0.476 0.588 19.04 1.23
2 F002 27 0.454 0.55 18.18 1.22
3 F003 28 0.434 0.526 17.39 1.21
4 F004 29 0.4 0.526 24.00 1.31
5 F005 30 0.416 0.526 20.83 1.26
6 F006 27 0.416 0.526 20.83 1.26
7 F007 26 0.476 0.555 14.28 1.16
8 F008 26 0.476 0.555 14.28 1.16
9 F009 25 0.454 0.500 9.09 1.16
10 F010 25 0.454 0.500 9.09 1.11
Table No. 6 :“Evaluation of post compression parameters of formulations F001-F010”
S.No Formulation
Codes
Thickness
(mm)
Diameter
(mm)
Weight
variation
(mg)
Hardness
(kg/cm2)
Friability
(%)
Disintegrati
on Time
(sec)
Wetting
Time
(sec)
Water
Absorption
Ratio (%)
1 F001
3.52 ± 0.06
8.03 ±
0.01
201..29 ±
1.02
4.99 ±
0.21
0.23
± 0.04
49 ± 2.00
51 ± 1
75.02 ± 0.28
2 F002
3.53 ±
0.25
8.03 ±
0.03
199.63 ±
1.89
4.89 ±
0.30
0.23 ±
0.02
33 ± 1.34
32 ± 2
95.43 ± 0.67
3 F003
3.53 ±
0.01
8.03 ±
0.02
200.12 ±
1.55
5.01 ±
0.12
0.24 ±
0.07
23 ± 1.10
25 ± 1
121.04 ±
0.45
4 F004 3.54 ±
0.54
8.03 ±
0.2
199.5 ±
0.37
4.98 ±
0.21
0.25 ±
0.24
60 ± 1.32
54 ± 1
71.23 ± 0.28
5 F005 3.53 ±
0.23
8.03 ±
0.1
198.2 ±
0.23
4.99 ±
0.75
0.25 ±
0.01
40 ± 1.32
52 ± 1
92.75 ± 0.33
6 F006 3.53 ±
0.24
8.02 ±
0.2
199.1 ±
0.12
4.91 ±
0.12
0.26 ±
0.23
28 ± 1.24
38 ± 2
101.1 ± .32
7 F007 3.55 ±
0.21
8.02 ±
0.02
199.12 ±
0.45
5.02 ±
0.24
0.22 ±
0.02
36 ± 1.16
37± 1
84.55 ±
0.58
8 F008 3.55 ±
0.01
8.03 ±
0.02
199.80 ±
0.21
5.10 ±
0.27
0.23 ±
0.05
24 ± 1.15
29 ± 1
128.24 ±
0.60
9 F009 3.52 ±
0.02
8.03 ±
0.01
201.1 ±
0.52
5.19 ±
0.11
0.24 ±
0.01
16 ± 1.12
24 ± 1
150.90 ±
0.10
10 F010 3.53 ±
0.05
8.03 ±
0.00
200.8 ±
0.20
5.12 ±
0.21
0.23 ±
0.01
16
± 1.00
24 ± 1
151.89 ±
0.30
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IN-VITRO DISSOLUTION STUDIES
Dissolution studies were carried out for 45 minutes in hydrochloric acid buffer of pH 1.2 (0.1N HCl
acid buffer). The samples were analyzed using spectrophotometer at 231 nm and the results are
shown below.
The dissolution profiles of all 10 formulations showed 80% release of the drug within 20 minutes.
It was observed that formulation F009 and F010 containing 5% crosspovidone as super disintegrant
showed maximum release of 100.01% in 45 minutes.
In-vitro dissolution studies of formulations F001, F002 and F003 in 0.1N HCl buffer
Table No. 7 :“In-Vitro Dissolution Studies of Formulations F001, F002 and F003 in 0.1N HCl Buffer”
S.NO Time Reference F001 F002 F003
(min) Product
1 0 0 0 0 0
2 5 72.29 55.2 59.9 62.5
3 10 87.91 64.2 69.7 76.9
4 15 92.33 71.1 77.6 83.76
5 20 95.10 80.0 84.2 90.1
6 30 98.30 91.3 93.1 94.29
7 45 100.1 97.9 97.1 98.1
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In-vitro dissolution graph of formulations F001, F002 and F003 in 0.1N HCl buffer
Figure 7: In-vitro dissolution graph of formulations F001, F002 and F003 in 0.1N HCl buffer.
In-vitro dissolution studies of formulations F004, F005 and F006 in 0.1N HCl buffer:
Table No. 8 :“In-vitro dissolution studies of formulations F004, F005 and F006 in 0.1N HCl buffer”
S. No Time Reference F004 F005 F006
(min) Product
1 0 0 0 0 0
2 5 72.29 51.37 55.90 61.32
3 10 87.91 61.90 65.71 75.49
4 15 92.33 71.12 73.20 81.02
5 20 95.10 80.10 84.01 87.57
6 30 98.30 85.90 90.82 92.49
7 45 100.1 94.10 96.97 98.56
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In-vitro dissolution graph of formulations F004, F005 and F006 in 0.1N HCl buffer:
Figure 8: In-vitro dissolution graph of formulations F004, F005 and F006 in 0.1N HCl buffer.
In-vitro dissolution studies of formulations F007, F008, F009 and F010 in 0.1 N HCl
buffer:
Table No. 9 :“In-vitro dissolution studies of formulations F007, F008, F009 and F010 in 0.1N HCl
buffer”
S. No Time Referrence F007 F008 F009 F010
(min) product
1 0 0 0 0 0 0
2 5 72.29 57.8 61.5 67.3 66.98
3 10 87.91 66.1 71.8 84.92 84.60
4 15 92.33 74.3 83.3 91.12 91.98
5 20 95.10 81.2 88.1 93.95 93.97
6 30 98.30 94.1 94.8 97.79 97.71
7 45 100.1 98.7 99.0 100.01 100.0
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In-vitro dissolution graph of formulations F007, F008, F009 and F010 in 0.1N HCl buffer:
Figure 9: In-vitro dissolution graph of formulations F007, F008, F009 and F010 in 0.1N HCl buffer.
STABILITY STUDIES
Table No. 10 :“Stability Studies For Optimized Formula (F010) at Different Conditions”
S.No Tests 25 ºC /60% RH 30º C/ 65% RH 40 ºC/ 75% RH
1 m 2 m 3 m 1 m 2 m 3 m 1 m 2 m 3 m
1. Hardness 5.12 ± 5.11 ± 5.11 ± 5.12 ± 5.09 ± 5.09 ± 5.10 ± 5.09 ± 5.08 ±
0.21 0.13 0.09 0.21 0.03 0.08 0.12 0.11 0.21
2. Friability 0.23 0.23 0.24 0.23 0.24 0.24 0.23 0.24 0.25
3. Thickness 3.53 ± 3.53 ± 3.52 ± 3.53 ± 3.52 ± 3.52 ± 3.53 ± 3.52 ± 3.51 ±
0.05 0.04 0.09 0.05 0.02 0.06 0.09 0.05 0.02
4. Diameter 8.03 ± 8.03 ± 8.03 ± 8.03 ± 8.03 ± 8.03 ± 8.03 ± 8.03 ± 8.03 ±
0.00 0.00 0.01 0.01 0.03 0.03 0.01 0.02 0 02
5. Weight 200.8 200.8 200.7 200.8 200.7 200.7 200.7 200.7 200.7
± 0.20 ± 0.11 ± 0.13 ± 0.20 ± 0.15 ± 0.20 ± 0.22 ± 0.21 ± 0.20
6. Disintegration 16 ± 16 ± 16 ± 16 ± 16 ± 16 ± 16 ± 16 ± 16 ±
1.0 0.9 1.0 1.0 0.8 0.3 0.3 1.0 1.0
Where, m = month
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DISSOLUTION PROFILE
Table No. 11 : “In-vitro Dissolution Profile of Stability Charged F010 Formulation For 1month, 2month” and 3
month in 40 ºC/ 75% RH:
S.NO Time Reference 40 ºC/ 75% RH
1 Month 2 Month 3 Month
1. 0 0 0 0 0
2. 5 72.29 66.76 66.55 65.66
3. 10 87.91 84.51 84.46 84.23
4. 15 92.33 91.89 91.02 90.62
5. 20 95.10 92.99 92.89 92.35
6. 30 98.30 97.21 96.97 96.56
7. 45 100.1 100.0 100.0 100.0
In-vitro dissolution graph of stability charged F010 formulation for 1 month, 2 month and 3
month in 40 ºC/ 75% RH stability condition:
Figure 10: In-vitro dissolution graph of stability charged F010 formulation for 1 month, 2 month and 3 month in
40 ºC/ 75% RH stability condition
DISCUSSION
Cetirizine is a metabolite of hydroxyzine. It is a second generation antihistamine (selective inhibitor
of peripheral H1receptors) which is currently marketed as a nonprescription product for adults and
children 2 years and older. This is marketed in several formulations (5 mg and 10 mg tablets and
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chewable tablets and 1 mg /mL syrup). But only one formulation regarding ODT is available in the
market. The present study is planned to develop ODT formulation intended to provide an
alternative dosing option for consumers that does not necessitate swallowing a tablet and that
allows for consumption with or without water.
In the present study ODT formulation of Cetirizine dihydrochloride prepared by direct compression
method was planned. As ODT defines to be disintegrated within 30sec and rapid disintegration of
tablet in the oral cavity is desired, super disintegrating agents along with other suitable excipients
were first selected. Direct compression method was employed in the study due to its cost
effectiveness and ease compared to other sophisticated methods. Another particular difficulty in the
formulation of Cetirizine dihydrochloride in oral pharmaceutical compositions is its unpleasant,
strong bitter taste. It is therefore desirable to develop ODT tablets of Cetirizine dihydrochloride,
which is having taste masking properties and rapid release of drug from tablet and allowing rapid
absorption in the body after oral administration.
The taste masking was carried out with ion exchange resin that is, Kyron T-114. It is weak acidic
methacrylic acid polymer. It is insoluble in water. It has got carboxyl functionality which enables it
to use for taste masking.
Different ratios of drug and polymer were used for drug loading on to the resin. The different ratios
used were 1:1, 1:2, 1:3 and 1:4. A ratio of 1:1 was first tried. In this trial maximum amount of the
drug loading was failed which could be seen in the percentage yield. So, a second ratio of 1:2 was
tried. In this trial the drug loading was better than the previous ratio, which can be compared by
increase in the percentage yield. A further trial was done using ratio of 1:3 for achieving better drug
loading. In this trial further increase in amount of the drug loading took place. Further ratio of 1:4
was taken to see whether more drug loading will take place or not. It was found that no further drug
loading was taking place. Hence, 1:3 ratio was finalized for the formulations. And also the bitter
taste of the drug was also masked. It was confirmed with the help of FT-IR studies and release
pattern of drug from the DRC in salivary pH at 6.8. So, the ratio of 1:3 of DRC was used for further
formulations to achieve a good tablets.
Development of the formulation in the present study was mainly based on Direct Compression, and
different superdisintegrants with their different concentration range were used for enhancing
disintegration time. The different superdisintegrants with their different concentration range were
used to get tablet with good physical properties and with minimum disintegration time. And also to
get good analytical (release profile) parameters of the tablets along with stability.
A total of ten formulations of ODT of Cetirizine dihydroichloride were prepared by direct
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compression as described in methodology section. Different super disintegrants used were
croscarmellose sodium, sodium starch glycolate and crospovidone each with a percentage range of
1, 3 and 5 of the tablet weight. Diluent (Mannitol), sweetener (Aspartame), flavoring agent
(Peppermint flavor) and lubricant (Magnesium stearate)were used in all the formulations. Of these,
the formulation with 5% crospovidone showed a better result
According to the Hand Book of Pharmaceutical Excipents the percentage range of the three selected
superdisintegrants were found to be within 5%. So, a minimum, a median and a maximum
percentage range were selected in the formulation process.
In F009 formulation, 5% of crospovidone was used as superdisintegrant. All the pre-compression
parameters showed good results. In the post compression parameters the disintegration time and
%CDR were found to be matching with the reference product. Hence, a reproducibility batch was
planned to check whether same results could be obtained.
In F010 formulation, the same percentage of superdisintegrant was used and rest of the excipients
were also the same range. All the pre-compression parameters showed excellent results same as the
F009 formulation. The disintegration time and %CDR were found to be 16 seconds and 100%
respectively which matches the reference product specifications. Hence, by this criteria F010
formulation as considered to be a better formulation for ODT of Cetirizine dihydrochloride. And
also all the post compression parameter of the ten formulations were found to be in good range.
So, F010 formulation was kept for stability studies at 25 ºC /60% RH, 30º C/ 65% RH and 40 ºC/
75% RH. Then the post compression parameters were checked again. All the post compression
parameters were in the same range. The dissolution parameters were also checked. 1 month, 2
month and 3 month stability data of 40 ºC/ 75% RH conditions were matching the reference
product. Hence, the formulation F010 was found to be matching with the reference product in all
aspects. So, F010 formulation can be concluded as he optimized formulation.
CONCLUSION
In the present work, a H1 antihistaminic drug, Cetirizine dihydrochloride was incorporated and
formulated in the form of orally disintegrating tablets. Cetirizine dihydrochloride is used in the
symptomatic treatment of allergenic conditions like cough, common cold and rhinitis.
The drug is very bitter to taste hence, taste masking of the drug has to be done. Ion exchange
method is one kind of taste masking technique used for taste masking. The ion exchange resin used
in the present study is Kyron T-114 which is weak cationic resin. Different ratios were used for
drug loading. In that, 1:3 was found to be having maximum loading capacity. Using this ratio of
DRC, formulations were formulated.
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Different super disintegrants were used in different concentrations. Of these formulation F009
containing 5% crospovidone showed good disintegration time of 16 seconds and dissolution
showing 100.01% release of drug in 0.1 N HCl acid buffer solution. A reproducibility batch of
F009 was taken that is F010 formulation to confirm whether perfect release of drug was there or
not. The formulation F010 also showed the same drug release profile as of reference product.
Hence, taste masking with ion exchange resin proved to be better method of masking the taste. And
also, in comparison of different concentrations of different super disintegrants, formulation F010
containing 5% crospovidone showed the best results. Hence, this can be concluded as the optimized
formulation and this formulation can be pipelined for production and used as best alternative to the
marketed formulation that is, Zyrtec® Allergy by the company Mcneil Consumer.
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