FORMULATION AND EVALUATION OF ORALLY DISINTEGRATING .... RPA1516246015.pdf · reported which implement complexation3,4, freeze-drying5, microencapsulation6,7, fluidized bed coating8,9,

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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.



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®



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.



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



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



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.



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



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.



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.



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.



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



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.



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



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



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



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



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



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



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



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



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.



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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FORMULATION AND EVALUATION OF ORALLY DISINTEGRATING .... RPA1516246015.pdf · reported which implement complexation3,4, freeze-drying5, microencapsulation6,7, fluidized bed coating8,9,