Formulation Optimization and Evaluation of Orodispersible Tablets of An Antipsychotic Drug Using Solubility Enhancement Technique

ISSN No:2321 8630, V 1, I 1, 2014
Journal Club for Pharmaceutical Sciences (JCPS)

Manuscript No: JCPS/RES/2014/11, Received on: 02/08/2014, Revised on: 07/08/2014, Accepted on: 11/08/2014
RESEARCH ARTICLE
Formulation Optimization and Evaluation of Orodispersible Tablets of an
Antipsychotic Drug Using Solubility Enhancement Technique
Chauhan KV*1, Kadliya PN1, Patel BA1, Patel KN1, Patel PA1
1
Depatment of Pharmaceutics, Shree Swaminarayan Sanskar Pharmacy College,
Zundal, Gandhinagar, Gujarat, India
ABSTRACT
The main objective of this study is to formulate oro dispersible tablets of Olanzapine and to
complex Olanzapine with -cyclodextrin (-CD) and PVP K 30. Olanzapine is second
generation atypical antipsychotic drug. Phase solubility studies demonstrated that addition of
water soluble polymer PVP K 30 with -CD further enhanced solubility of drug compared to
-CD without PVP K 30. Complex was characterized using infrared spectroscopy,
differential scanning calorimetry, % drug release study, % drug content and saturated
solubility study. A 32 full factorial design was applied to systematically optimize the drug
disintegration time. The concentration of Croscarmellose Sodium (X1) and concentration of
Kyron T 314 (X2) were selected as independent variables. The disintegration time (Y1) and
wetting time (Y2) were selected as dependent variables. The prepared tablets were evaluated
for hardness, friability, disintegration time, wetting time and In-vitro drug release. The
different formulations showed disintegration time between 19 to 48 seconds. The results
indicated that concentration of croscarmellose Sodium (X1) and concentration of Kyron T
314 (X2) significantly affected the disintegration time (Y1) and wetting time (Y2).Regression
analysis and numerical optimization were performed to identify the best formulation.
Formulation F18 prepared with Croscarmellose Sodium (4.47 %) & Kyron T 314 (3.73 %)
was found to be the best formulation with disintegration time 20 sec, wetting time 26 sec and
% drug release in 10 min 99.49%.
KEYWORDS
Olanzapine, Orodispersible tablet, -cyclodextrin, Croscarmellose sodium, Kyron T 314,
Disintegration time, Wetting time, 32full factorial design
INTRODUCTION
forms is Dysphagia or difficulty in
Introduction to Drug Delivery System
swallowing for many patients; however,
The oral route remains the preferred route
hand
for administration of therapeutic agents.
underdeveloped muscular and nervous
One important drawback of such dosage
systems in young individuals, children and
tremors,
geriatric
patients,
the
in case of uncooperative patients, the

*Address for Correspondence:
Krishna V. Chauhan,
Department of Pharmaceutics, Shree
Swaminarayan Sanskar Pharmacy College,
Zundal, Gandhinagar, Gujarat, India.
E-Mail Id: krishna_chauhan0123@yahoo.in
Copyright reserved by Journals Club & Co.
problem
of
swallowing
is
common
phenomenon. For example, a very elderly

patient may not be able to swallow a daily
dose of antidepressant; a schizophrenic
33
Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique
patient can hide a conventional tablet
with dysphagia are not able to swallow
under his or her tongue to avoid its daily
conventional Olanzapine tablet.
dose of an atypical anti-psychotic. Orally
To overcome this problem an attempt was
disintegrating tablets (ODTs) are a perfect
made
fit for all these patients.
ODTsinclusion
to
complex
formulate
of
and
evaluate
complex.
Olanzapine
Inclusion
with
The Center for Drug Evaluation and
cyclodextrin was made to improve the
Research (CDER), US FDA defined Oral
aqueous solubility of Olanzapine and to
Disintegrating Tablets (ODT) as A solid
enhance dissolution rate of Olanzapine. It
dosage
medicina
may enhance the pregastric absorption of
lsubstances, which disintegrates rapidly,
Olanzapine. -cyclodextrin may act as
usually within a matter of seconds, when
channel forming agent because it helps in
placed upon the tongue.
quick disintegration of tablets and may act
Olanzapine is second generation atypical
as permeation enhancer to pass Olanzapine
antipsychotic
through
form
containing
drug
classified
as
oral
mucosa.
Tablets
were
thiobenzodiazepines. It is D2 and 5 HT2
prepared by using -cyclodextrin and four
receptor antagonist mainly used drug used
super disintegrants, namely as SSG,
in the treatment of schizophrenia and
croscarmellose sodium, crospovidone and
bipolar disorder. In this type of disease
Kyron T 314. Super disintegrants are
require rapid onset of action in order to
added to facilitate drug release and
control on mental condition.
It is
consequently improve the solubility of
practically insoluble in water, having only
Olanzapine. Tablets were prepared by
60%
Olanzapine
using direct compression technique. The
undergoes extensive first pass metabolism.
simplicity and cost effectiveness of the
It has less extra pyramidal side effects
direct
compared to other antipsychotics.Further,
positioned
Olanzapine has a small dose, optimum
alternative to granulation technologies.
oral
bioavailability.
molecular weight, unionized at salivary pH

and a long elimination half life (21-54
compression
direct
technique
compression
have
as
an
MATERIALS & METHODS

Experimental Work
hour).Some schizophrenic patients hide a

conventional tablet under their tongue to
Materials
avoid its daily dose of an atypical
Olanzapine and other excipients were
antipsychotic. Also schizophrenic patients
gifted
from
West-Coast
Pvt.
Ltd.,
34
Ahmedabad, Avicel pH 112 and Mannitol

SD 200 were gifted from Torrent Research
appropriately
diluted.
The
OLP
concentration was determined using a UV

visible spectrophotometer in 226.8 nm.
Centreand Kyron T 114 was gifted by

Corel Pharma Chem., Ahmadabad.
Experiments were performed in triplicate.

The graph was plotted against drug
concentration
DRUGEXCIPIENTS
vs.
betacyclodextrin.
COMPATIBILITY STUDY
determined
by
FT-IR
The
blanks
of
were
prepared using the same concentration of
Compatibility of the drug with excipients

was
concentration
spectral
betacyclodextrin with or without water

soluble polymer in distilled water so as to
cancel out any absorbance that may be
analysis, this study was carried out to

detect
any
changes
on
chemical
constitution of the drug after combined it
exhibited by betacyclodextrin.
Preparation of Inclusion Complex
Kneading Method
Required quantities of the Olanzapine and
with the excipients. The samples were

taken for FT-IR study.
and 1:4 molar ratios and thoroughly mixed

with or without water soluble polymer. A
Methods
Phase Solubility Analysis for Olanzapine
Phase solubility studies were performed
according to the method reported by
Higuchi and Connors.Various aqueous
solutions (0.2%, 0.4%, 0.6%, 0.8% and 1%
w/v) of the betacyclodextrin was prepared
with and without water soluble polymer
PVP K 30 and PEG 4000( 5% w/v) and
10 ml of these solution, excess quantities
of Olanzapine (20 mg) were added. The
solutions were kept for shaking for 24 h
using
lab
-CD were weighed to give 1:1, 1:2, 1:3
shaker.
After
complete
equilibration the supernatant solution were

collected carefully and filtered using
Whatman filter paper (No. 41) and
homogeneous paste of Olanzapine and CD was prepared by adding water: ethanol

(50: 50) in small quantities. The paste was
kneaded for 60 min and dried in hot air
oven at 45-50C. The dried complex was
sieved through 60# and evaluated. The
optimized complex was further prepared
by addition of water soluble polymer PVP
K 30. It was added at a concentration of
5%, 10% and 15% of the solid complex.
Characterization of Complex
Inclusion complex was characterized and
evaluated using following techniques.
Fourier
Transform
Infrared
(FTIR)
Spectroscopic Analysis
35
The Fourier transform infrared spectrum of
and 50 rpm in Phosphate buffer (pH 6.8).
moisture
of
At fixed time intervals, 10 ml aliquots
Olanzapine, -CD, PVP K 30 and kneaded
were withdrawn, filtered, suitably diluted
complex
IR
and then assayed for Olanzapine content
spectrophotometer by potassium bromide
by measuring the absorbance at 226.8 nm.
(KBr) pellet method.
Fresh media (10 ml), which was pre-
Differential Scanning Calorimetry (DSC)
warmed at 37 C, was replaced in to the
Analysis
dissolution medium after each sampling to
DSC scans of the powdered samples were
maintain its constant volume throughout
recorded. The thermal traces were obtained
the
by heating the complex from 40 to 350 C
performed in three replicates (n = 3), and
at heating rate of 10 C under inert
calculated mean values of cumulative drug
nitrogen
release were used while plotting the
free
powdered
recorded
dynamic
sample
on
atmosphere
(100
test.
Dissolution
studies
ml/min) in open aluminium crucibles.
release curves.
Drug Content Estimation 7
Saturation Solubility Study
Olanzapine
betacyclodextrin
were
complex,
Saturation solubility study was performed
equivalent to 10 mg of drug, was weighed
according to method reported by Higuchi
accurately and added to 100 ml volumetric
and
flask. To this solution add small amount of
inclusion complex were added to 25 mL
ethanol. These solutions were stirred for
distilled water in glass stoppered conical
60 mi, till the entire drug leached out then
flasks and shaken for 24 h in rotary flask
make the volume up to mark with
shaker. After shaking the solutions were
phosphate buffer 6.8. Then this solution
filtered through Whatman filter paper No.
was filtered. 0.5 ml of solution withdrawn
41.
and added into 10 ml of volumetric flask
spectrophotometrically at 226.8 nm. Each
and volume was made to 10 ml (5 m/ml)
sample was done in triplicate.
Connors.
The
Excess
filtrate
quantities
was
of
analyzed
with phosphate buffer pH 6.8. Drug

content was estimated by UV visible
Formulation and Evaluation of Tablets
spectrophotometer at 226.8 nm using
Selection of super disintegrant
phosphate buffer pH 6.8 as blank.
In preliminary trial batches, different
Dissolution Study6, 7
concentrations i.e. 2 and 4% of Sodium
Dissolution studies were carried out using
starch glycolate (SSG), Crospovidone
a USP dissolution apparatus type II with
(CP), Croscarmellose sodium (CCS) and
900 ml dissolution mediums at 37 C 0.5
Kyron T 314 were screened. From the all
36
the four super disintigrants CCS and

Kyron T 314 had shown less disintegration
Bulk density =Weight of the powder /

Volume of the packing
time and wetting time compared to SSG

Tapped Density
and CP.
Method - Direct Compression Method
Weighed quantity of powder blend was
According to the formula given in table1
taken into a graduated cylinder and volume
all the ingredients (without magnesium
occupied by powder blend was noted
stearate and aerosil) were passed through
down. Then cylinder was subjected to 500,
#40 mesh separately. Required quantity of
750 and 1250 taps in tap density tester
each excipient was weighed accurately and
According to USP the blend was subjected
blend was mixed thourouly. Lubricants i.e.
to 500 taps. The %volume variation was
aerosil and magnesium stearate were
calculated and subjected for additional 750
passed through 80# and mixed them to
taps and %volume variation is calculated.
above
Tapped density= Weight of the powder /
blend.
Powder
blend
was
compressed using 9 mm concave punch on
volume of the tapped packing
rotary tablet machine.

Evaluation Parameters of Powder Blends
Orally
disintegrating
tablets
are
manufactured by several processes but for

all of them, first a blend of various
ingredients (APIs and excipients) is made.
The quality of tablet, formulated is
generally depending upon the quality of
Carrs compressibility index

The compressibility index of the blends
will
be
determined
by
Carrs
compressibility index.
Carrs compressibility index (%) =
Carrs compressibility index (%) =
Tapped density-Bulk density X 100
physicochemical properties of blends.

Tapped density
There are many formulation and process

variables involved in mixing and all these
can affect the characteristics of blends
Hausner's ratio
produced. The various characteristics of
Hausner's ratio is an index of ease of
blends tested are as given below.
powder flow. It is calculated by following
Bulk density
Apparent bulk density was determined by
pouring 10 gm of powder blend into
graduated cylinder and measuring the
formula.
Hausner's ratio = Tapped density / Bulk
density
volume.
37
Angle of repose
weight tablets were being made. Twenty
Angle of repose () is a measure of
tablets were selected randomly from each
flowability of material. It was determined
formulation, weighed individually and the
using fixed height funnel method. A glass
average weight and % variation of weight
funnel was placed with its tip positioned at
was calculated.
a fixed height (h) above a graph paper on a
Disintegration Time
horizontal surface. The blend was poured
The USP device to test disintegration has
through a funnel until the apex of conical
six glass tubes that are 3 long, open at the
pile touched the tip of the funnel. The
top, and held against 10 screen at the
radius of the pile (r) was measured and
bottom end of the basket rack assembly.
angle of repose was calculated as follows.
One tablet is placed in each tube and the
= tan-1 (h/r)
basket rack is poisoned in 1 liter beaker of

distilled water at 37 2 C, such that the
Where, = angle of repose
tablets remain below the surface of the
h = height of the pile
liquid on their upward movement and
r = average radius of the powder cone
descend not closer than 2.5cm from the
Evaluation of Tablets
bottom of the beaker. The time required to
Thickness
The
thickness
of
the
tablets
was
obtain complete disintegration of all the

tablets will be noted.
determined using a vernier caliper.

Hardness
Hardness
was
measured
using
the
Monsanto hardness tester. Measure the

pressure required to break diametrically
placed matrix tablet, by a coiled spring. It
is expressed in kg/cm2.
Friability
Friability of the tablets was determined
using Roche friabilator. It is expressed in
%
Weight Variation
It was performed as per the method given
in the Indian pharmacopoeia. Tablets were
randomly checked to ensure that uniform
Wetting Time
A small piece of tissue paper folded twice
will be placed in a small petridish
containing 6ml of water. A tablet will be
put on the paper and the time required for
complete wetting was measured.
% Drug Content7
Three tablets were accurately weighed and
finely powdered. A quantity equivalent to
10 mg of Olanzapine was transferred to a
100 ml volumetric flask. To it, 50 ml of
ethanol was added and shaken for 1 hour
to dissolve drug. The solution was filtered
and residue was washed with 25 ml of
38
ethanol. The washing obtained was added
each at 3 levels, and experimental trials
to initial filtrate and volume was made up
were
to 100 ml with ethanol. From above
combination. In the preliminary trial runs,
solution 0.5 ml of stock solution was
5 % Cross carmalose sodium and 4 % of
diluted to 100 ml of phosphate buffer pH
Kyron T 314 showed good results. So
6.8. The drug content was determined
these levels were selected and subjected to
spectrophotometrically at 226.8 nm.
further
Dissolution Studies 7
sodium and Kyron T 314were selected as
Dissolution studies were carried out for all
independent factors whereas disintegration
the formulation combinations in triplicate,
time (DT) and wetting time (WT) were
employing USP XXIII paddle method
measured as responses. The polynomial
(Apparatus 2) using phosphate buffer pH
equation can be used to draw conclusions
6.8, as the dissolution medium (900 ml) at
after
50 rpm and 37 0.5C. An aliquot of
coefficient and the mathematical sign. The
sample was periodically withdrawn at
responses were analyzed for ANOVA
suitable
volume
using Design Expert version 8.0.5. A
replaced with equivalent amounts of plane
mathematical equation was generated for
dissolution medium. The samples were
each
analyzed spectrophotometrically at 226.8
mathematical models were tested for
nm.
significance. Response surface plots were
Full Factorial Design
generated for each response to study the
A 32 Factorial design was chosen for the
behaviour of the system.
time
intervals
and
performed
at
all
optimization.
considering
response
possible
Cross carmalose
the
magnitude
parameter.
of
The
current formulation optimization study. In

this design two factors were evaluated,
Table 1: Selection of Levels for Independent Variables and Coding of Variable

INDEPENDENT VARIABLES
Levels
Coded value
Low
X1 (%)
X2 (%)
-1
Intermediate
High
39
Table 2: Factorial Design Layout and Data Transformation for Factorial Batches
Run
Independent
Independent Variable in
Variables in
actual form
Dependent variable
coded form
Factor
Factor
Cross
Kyron T
Disintegration
Wetting
carmalose
314
Time (Sec.)
Time (Sec.)
sodium
1
-1
-1
480.35
540.52
-1
330.42
390.56
-1
290.39
350.43
-1
410.45
490.49
280.58
330.39
240.65
300.32
-1
340.43
400.46
230.59
290.39
190.52
250.78
Table 3: Formulations using 32Factorial Design

FORMULATION
F1
F2
F3
F4
F5
F6
F7
F8
F9
Olanzapine --CD PVP K
130.
130.
130.
130.
130.
130.
130.
130.
130.
30 complex
88
88
88
88
88
88
88
88
88
Croscarmellose sodium
2.5
2.5
2.5
7.5
7.5
7.5
12.5
12.5
12.5
Kyron T 314
10
10
10
Microcrystalline cellulose
50
50
50
50
50
50
50
50
50
Aspartame
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
Aerosil
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
Mg stearate
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
Mannitol SD 200
61.
56.
51.
56.
51.
46.
51.
46.
41.
62
62
62
62
62
12
62
62
62
INGREDIENTS
pH 112
Total Weight
250(mg/tablet)
40
Validation of statistical model
validate RSM. The tablets were formulated
From overlay plot of responses, optimized
using chosen optimal composition &
formulation was selected as checkpoint to
evaluated for DT & WT.
Table 4: Composition of Optimized Formulation

FORMULATION INGREDIENTS
F10
Olanzapine--CD-PVP K 30 complex
130.88
MCC PH 112
50
Croscarmellose sodium
11.17
Kyron T 314
9.32
Aspartame
1.25
Aerosil
1.25
Magnesium stearate
2.5
Mannitol up to.
250 mg
Stability Study of Optimized Batch
between 50 and 100. The dissolution
Stability study was carried out for the
profiles
optimized formulation for 25 2oC/ 60 5
following formula,
of products
were
compared
% RH and 40 2oC/ 75 5 % RH for 1
months and samples were withdrawn at the
f2 = 50 x log {[1+(1/n) | Rj Tj | 2 ] -
end of 0, 1, 2, 3 and 4 week and evaluated
0.5 x 100}
for active drug content, disintegration
j=1
time, wetting time and Invitro drug release.
Where,
Comparison of Optimized Formulation
n = number of time points
with Market Product Using Similarity
Rj = Dissolution value of the reference
Factor (f2)
batch at
The similarity factor (f2) given by SUPAC
time t
guidelines for modified release dosage
Tj = Dissolution value of the test batch at
form was used as a basis to compare
time t.
dissolution profile. The dissolution profiles

are considered to be similar when f2 is
RESULT AND DISCUSSION

Identification of Drug by FT - IR
41
Fig 1: FTIR Spectra of Olanzapine
Drug-Excipients Compatibility Study by

FT - IR
Fig 2: FTIR Spectra of Olanzapine and Excipients
A Drug + Sodium starch glycolate
FTIR
spectra
of
Olanzapine
show
E Drug + Kyron T 314
characteristic bands are attributed to the
B - Drug + Crosspovidone
stretching of different group vibrations:
F Drug+ MCC pH 112
3247.27 cm-1 stretching of the N-H band
C Drug + Croscarmellose sodium
2930.2 cm-1 stretching of the N-H band
G Drug + Mannitol SD 200
1586.16 cm-1 stretching of the C=C band

1290.14 cm-1 stretching of the C-N band
759.81 cm-1 band due to O-disubstituated
Interpretation
To study the compatibility of drug with
benzene
excipients
The IR spectrums of Olanzapine and its
IR
spectra
of
drug
in
combination with excipients in 1:1 ratio
combination
was studied prior to preparation of
croscarmellose, etc. were shown in Figures
Olanzapine orally disintegrating tablets.
indicate
with
that
crospovidone,
there
was
no
42
physicochemical interaction in between
characteristics bands were presented in
drug and studied excipients because all
physical mixture.
Phase Solubility Study
Conc. of Olanzapine(mg/ml)
Fig 3: Phase Solubility of Olanzapine

0.004
0.0035
0.003
y = 0.1796x + 0.0017
R = 0.977
y = 0.2069x + 0.0018
R = 0.9608
0.0025
0.002
0.0015
0.001
0.0005
y = 0.172x + 0.0017
R = 0.9926
-CD
-CD with
PVP K 30
0
0
0.002 0.004 0.006 0.008

Concentration of -CD(mg/ml)
-CD with
PEG 4000
0.01
From the Phase solubility analysis it was
Characterization
concluded that as the concentration of
cyclodextrin-PVP K 30 Complex
betacyclodextrin increased concentration
Drug Content Estimation
of Olanzapine is also increased. According
The drug content of inclusion complex
to Higuchi and Connors, the obtained
prepared by kneading was found 94.44
curve was AL type of solubility curve.
%1.25to 97.25 % 1.10.
Addition of the water soluble polymer like
Saturation Solubility Study
PVP
In the present work, enhancement in the
30
and
PEG
4000
with
Olanzapine--
betacyclodextrin solubility of the drug was
solubility
further increased. The stability constant
inclusion complex. Solubility of pure
was found to be 122.19, 128.77 and 144.93
Olanzapine was found to be 0.03432.45
for -CD, -CD with PEG 4000 and -CD
mg/mL and solubility of complex was
with PVP K 30 respectively. From the
found to be 0.07653.36mg/mL.
graph it was concluded that solubility of
Fourier
the drug higher in case of PVP K 30
Spectroscopy
compare to PEG 4000. So PVP K 30 was
IR is a highly sensitive method of analysis,
selected
all spectra of complex showed some or
for
the
preparation
of the
complex.
was
of
observed
Transformation
in
case
of
Infrared
other changes from parent spectra (Figure

3). 3247.27 cm-1 stretching of the N-H
43
band, 2930.2 cm-1 stretching of the N-H
influenced
band, 1586.16 cm-1 stretching of the C=C
Absorption band at 3247.27 cm-1
band, 1290.14 cm-1 stretching of the C-N
completely disappeared in the complex
band 759.81 cm-1 band due to O-
spectra, which indicate that hydrogen bond
disubstituated benzene.
formation between hydroxyl group of
In
the
FTIR
spectra
of
by
complex
formation.
is
prepared
betacyclodextrin, PVP K 30 and amine
complexes, Olanzapine bands are almost
group of the drug. Reduction in intensity
completely obscured by very intense and
of the C=C band at 1586.16 cm-1.
broad CD bands, which are hardly
Fig 4: FTIR Spectra of (a) Drug (b) -CD (c) PVP K 30 (d) Physical mixture and (e)
Complex
Differential Scanning Calorimetry
130 C, which are related to evaporation of
Olanzapine
characteristic
water from the cyclodextrin. -CD also
196.50C,
shows small endo or exo effects at 297
corresponding to the Olanzapine melting
320 C due to thermal degradation. In
point and indicating that the drug is in a
DSC thermogram of Olanzapine- CD-
crystal polymorphic form. Furthermore, -
PVP K 30 Complex peak were disappeared
CD and PVP K 30 showed broad
which gave conformation of complex
endothermic
exhibited
peak
a
at
endothermic events in the range from 80 to
44
Fig 4: DSC Thermogram of (A) Olanzapine (B) Betacyclodextrin (C) PVP K 30 and (D)
Complex
Fig 5: Comparative Dissolution Profiles of Various Molar Ratios of Olanzapine--CD
% CDR
Complex
100
90
80
70
60
50
40
30
20
10
0
drug
1:1 M
1:2 M
1:3 M
1:4 M
0
10
20
30
40
50
60
Time (mins.)
Dissolution Study of Olanzapine and its
release compare to other molar ratios. So it
Inclusion Complex
was selected for the further preparation of
Based on the % CDR 1:3 M of the drug to
complex with PVP K 30.
betacyclodextrin was shown higher % drug
45
Fig 6: Comparative Dissolution Profiles of Various Molar Ratios of Olanzapine--CDPVP K 30

100
% CDR
80
1:3 M
60
PVP K 30 - 5%
40
PVP K 30 - 10%
20
PVP K 30 - 15 %
0
0
10
20
30
Time (mins.)
40
50
60
Based on % drug release from different
K 30 was optimized. The increase in the
molar ratios of complex Olanzapine: -
dissolution of Olanzapine with -CD and
cyclodextrin, 1:3 molar ratio with 10 %
PVP K 30 could be explained by the
PVP K 30 was selected as optimized ratio
principal
as it was shown 99.31 % drug release in 30
complex formation and the amorphous
min as compared to 1:3 with 5 % PVP K
form generation of Olanzapine. The high
30 molar ratio that was shown 99.50 %
solubility of -CD and PVP K 30 in water
release at the end of 60 min. 1:3 molar
resulted in better wettability of drug
ratio with 15 % PVP K 30was not shown
particles and local enhancement of its
significant increase in% drug release when
solubility
compare to 1:3 molar ratio with 10 % PVP
surrounding the drug particles.
of
at
hydrophilicity,
the
inclusion
diffusion
layer
K 30. So, 1:3 molar ratio with 10 % PVP
Table 5: Pre-Compression Evaluation Parameters of Powder Blend of Factorial Batches

Batch Code
Bulk
Density
(gm/ml)
Tapped
Density
(gm/ml)
Carrs
index
(%)
0.4410.032
0.4950.038
13.200.32
F1
0.4820.025
0.5520.019
12.720.13
F2
0.4900.017
0.5600.029
13.500.15
F3
0.4750.018
0.5390.09
12.320.29
F4
0.4800.010
0.5650.015
14.280.32
F5
0.4920.013
0.5540.023
12.910.19
F6
0.5030.017
0.5760.010
12.400.19
F7
0.4690.029
0.5370.016
13.200.15
F8
0.4760.019
0.5290.024
12.820.09
F9
All values are expressed as mean standard deviation, n=3
Angle of
repose
( )
Hausners
ratio
27.30.21
29.40.22
28.70.13
27.60.22
26.4030
1.130.29
27.80.18
27.10.25
26.20.22
27.30.15
1.140.19
1.140.16
1.120.14
1.160.25
1.120.20
1.140.16
1.150.13
1.120.10
46
Evaluation of Powder bland
and angle of repose ranged from 26.2 to
The powder blend for all nine formulations
29.4 . All these results indicate that, the
were evaluated for bulk density which
power blend possess good flowability and
ranged from 0.441 to 0.503, tapped density
compressibility properties. Hence, tablets
which ranged from 0.529 to 0.576, Carrs
were prepared using direct compression
index ranged
method.
from 12.32 to
14.28,
Hausners ratio ranged from 1.12 to 1.16
Evaluation of Tablets
Table 6: Physical Evaluation Parameters of Tablets of factorial batches

Batch
Weight
Hardness
Thickness
Friability
Drug Content
Code
Variation
(kg/cm2)
(mm) SD
(%)SD
(%) SD
(mg)SD,
SD
n=20
F1
Pass
3.2 0.23
4.950.02
0.480.02
99.481.15
F2
Pass
3.5 0.52
4.93 0.03
0.420.01
99.211.23
F3
Pass
3.4 0.29
4.950.02
0.370.04
99.671.73
F4
Pass
3.1 0.52
4.930.04
0.560.03
98.321.33
F5
Pass
3.5 0.59
4.970.01
0.490.01
98.531.39
F6
Pass
3.3 0.26
4.950.03
0.410.03
98.561.20
F7
Pass
3.5 0.52
5.150.02
0.390.02
99.141.31
F8
Pass
3.1 0.53
4.950.01
0.340.01
99.781.30
F9
Pass
3.2 0.28
4.930.02
0.460.03
98.231.14

All the tablet preparations were evaluated
weight
for various physical parameters before
pharmacopoeial limits of 5% of the
proceeding further. Table 6 includes the
weight. The weights of all the tablets were
values (mean SD) of weight variation,
found to be uniform with low standard
hardness, thickness and friability of eight
deviation values.
tablet batches prepared using different
Thickness of all tablets was in the range
combinations of functional excipients. All
between 4.93 mm to 5.15 mm. Hardness of
the eight batches passed weight variation
tablets was in range between 3.1 to 3.5
test. All the formulated (F9 to F17) tablets
kg/cm2.Friability was in range between
passed weight variation test as the %
0.34 to 0.56 %. Thus, all the physical
variation
was
within
the
47
parameters of the manually compressed
was observed in batches prepared using
tablets were quite within control. Friability
combination of CCS and Kyron T 314. As
values were less than 1 % in all cases
CCS combined with Kyron T 314, by
shows good mechanical strength at the
keeping concentration of CCS constant
time of handling and transports.
and increase concentration of Kyron T 314
The % drug content for tablets of all
from 0 to 4%, disintegration time was
formulation was found to be in the range
decreased as shown in result.
of 98.23 to 99.67%. Thus the assay of
The wetting time of tablets as shown in
Olanzapine was found to be quite within
Table 2 of all nine formulations was in the
the range.
range of 26 to 54 seconds. The wetting
The results shown in Table 2indicated that
time is closely related to the disintegration
concentration-dependent
time.
disintegration
Fig 7: Effect of Super disintegrants on Dissolution Profiles of Factorial Batches

(F1-F9)
100
% CDR
90
80
F1
70
F2
60
F3
50
F4
40
F5
30
F6
20
F7
10
F8
F9
0
10
15
20
25
30
Time(mins.)
The dissolution profiles of all the nine
3% and4 % Kyron T 314 was shown 94.52
formulations are shown in Figure 6.17.
and 99.09 % in 10 minutes. Combination
From graph it was concluded that as the
of
concentration
disintegrant
dissolution rate as compared to individual
increases, % drug release was also
super disintegrant. The release of drug was
increased. % drug release from F8 and F9
largely depended on the disintegration
of
super
two
disintegrates
also
improves
formulations prepared with CCS 5 % and
48
time. That is faster the disintegration of
Positive sign in front of terms indicate
tablets, better and faster is the release.
synergistic effecy while negative indicate
Factorial
antagonistic effect upon responses. So,
equation
for
Dependent
sign of b1 andb2 were negative shows that
Variables
as a concentration of CCS and Kyron T

1) Factorial equation for Disintegration
314 increases ,WT decreases. As the R2
Time
value nearer to 1 indicate selected model
Y= 27.89 5.50 X1 -8.33X2 +1.25X1X2 -
was significant.
0.17 X12 + 4.67 X22, R2= 0.9940
ANOVA for Quadratic Model for DT and

WT
Positive sign in front of terms indicate
ANOVA
synergistic effect while negative indicate
table
used
to
generate
mathematical models. The high values of
antagonistic effect upon responses.So, sign
correlation coefficient for DT and WT
of b1 andb2 were negative shows that as a
indicate a good fit i.e.good agreement
concentration of CCS and Kyron T 314
between the dependent and independent
increases , DT decreases. As the R2 value
variables. The mathematical model was
nearer to 1 indicate selected model was
evolved by omitting insignificant term (p
significant.
>0.05). So, the main effect X1 & X2 were
2) Factorial equation for Wetting Time
found significant as p value was < 0.05.
Y= 33.11 -5.67 X1 -8.67 X2 +1.25 X1X2

0.67X2 + 6.33 X22, R2= 0.9965
Table 7: ANOVA Response Surface Quadratic Model for Disintegration Time

p-value
Source
SS
df
MS
F Value
Model
648.03
129.61
451.53
0.0002
A CCS
181.50
181.50
632.32
0.0001
B-Kyron T 314
416.67
416.67
1451.61
<0.0001
AB
6.25
6.25
21.77
0.0186
A2
0.056
0.056
0.19
0.6897
B2
43.56
43.56
151.74
0.0012
Cor Total
648.89
prob > F
R2
0.9987
49
Table 8: ANOVA Response Surface Quadratic Model for Wetting Time

F
p-value
Value
prob > F
146.14
199.78
0.0006
192.67
263.39
0.00057
450.67
450.67
616.10
0.0007
AB
6.25
6.25
8.54
0.0613
0.89
0.89
1.22
0.3508
B2
80.22
80.22
109.67
0.0019
Cor Total
732.89
Source
SS
df
MS
Model
730.69
A - CCS
192.67
B-Dilution ratio
R2
0.9970
square (MS) to the appropriate error (i.e.

ANOVA Table shows the results of the
residual) mean square. The mathematical
analysis of variance (ANOVA), which was
model
used to generate mathematical models. The
insignificant term (p > 0.05). So, the main
high values of correlation coefficient for
effect X1 & X2 were found significant as p
DT and WT indicate a good fit i.e. good
value was < 0.05.
agreement between the dependent and
Response Surface Plots
independent variables. The F value in the
Effect of X1 and X2 on Disintegration
ANOVA table is the ratio of model mean
Time
was
evolved
by
omitting
Fig 8: Two-Dimensional Contour Curve for Disintegration Time

Design-Expert Software
Factor Coding: Actual
DT
Design Points
48
DT
4.00
Prediction
20
21.024
3.00
B: Kyron T 314
X1 = A: CCS
X2 = B: Kyron T 314
2.00
30
1.00
40
0.00
1.00
2.00
3.00
4.00
5.00
A: CCS
50
Fig 9: 3-D graph showing effect of CCS and Kyron T 314 on Disintegration Time (R1)
DT
Des ign points above predicted value
Des ign points below predicted value
48
21.024
20
X1 = A: CCS
X2 = B: Kyron T 314
50
40
DT
30
20
10
5.00
4.00
4.00
3.00
3.00
2.00
B: Kyron T 314
A: CCS
2.00
1.00
0.00
1.00
This contour plot shows the effect of
of X1 and X2 increases, the value of
concentration of croscarmellose (X1) and
response Y1 decreases.
concentration
Effect of X1 and X2 on Wetting Time
of
kyron
314
on
disintegration time (Y1). As concentration
Fig 10 : Two-Dimensional Contour Curve for Wetting Time

WT
Design Points
54
WT
4.00
Prediction
26
26.636
3.00
B : K yron T 314
X1 = A: CCS
X2 = B: Kyron T 314
30
2.00
1.00
40
50
0.00
1.00
2.00
3.00
4.00
5.00
A: CCS
51
Fig 11 : 3-D graph showing effect of CCS and Kyron T 314 on Wetting Time (R1)
WT
Des ign points above predicted value
Des ign points below predicted value
54
26.636
26
X1 = A: CCS
X2 = B: Kyron T 314
60
50
WT
40
30
20
5.00
4.00
4.00
3.00
3.00
2.00
A: CCS
2.00
1.00
B: Kyron T 314
0.00
1.00
This contour plot shows the effect of
time (Y2). As concentration of X1 and X2
concentration of croscarmellose (X1) and
increases, the value of response Y2
concentration of kyron T 314 on wetting
decreases.
Fig 12 : Overlay Plot of Response Variables

Overlay Plot
Overlay Plot
4.00
DT
WT
Design Points
DT:
WT:
X1
X2
3.00
B : K yro n T 3 1 4
X1 = A: CCS
X2 = B: Kyron T 314
21.024
26.636
4.47
3.73
WT: 26.000
2.00
WT: 35.000
DT: 30.000
1.00
0.00
1.00
2.00
3.00
4.00
5.00
A: CCS
From overlay plot of responses, optimized
concluded that by adopting systemic
formulation was selected as checkpoint to
formulation approach one can reach to an
validate RSM. The Overlay plot of
optimum point in shortest time with
responses generates an optimized area as
minimum effect. Thus, we can conclude
per desired criteria of DT should be 20 sec
that statistical model is mathematically
& WT should be 25 sec. So, it can be
valid.
52
Table 9: Evaluation Parameters of Optimized Formulation

PRECOMPRESSION EVALUATION PARAMETERS
Bulk density(gm/ml)
Bulk density(gm/ml)
Tapped density(gm/ml)
Tapped density(gm/ml)
Carrs compressibility index (%)
Carrs compressibility index (%)
Hausner ratio
Hausner ratio
Angle of repose()
Angle of repose()
EVALUATION PARAMETERS OF TABLETS

Weight variation
Weight variation
Hardness (kg/cm2)
Hardness (kg/cm2)
Thickness (mm)
Thickness (mm)
Friability (%)
Friability (%)
Disintegration time (sec)
Wetting time (sec)
Wetting time (sec)
% Drug content
% Drug content
Drug release (%) in 10 min
Drug release (%) in 10 min
Table 10: Comparison of Marketed Formulation with Optimized Formulation Prepared

by Direct Compression Method
Parameters
Marketed Preparation
Optimized formulation
Hardness(kg/cm2)
3.50.23
4.00.35
240.75
200.92
Wetting time (sec)
290.89
260.95
Q10(% Drug release in 10 min)
98.893.12
99.492.87
Fig 13: Comparative Release Profile between Marketed Formulation and Optimized
Batch (F10)
% Drug release
100
80
60
40
Optimized Batch
20
Marketed Product
0
0
4
6
Time (mins)
10
53
Similarity Factor
curves.
The
The similarity factor (f2) is a logarithmic
considered to be similar when f2 is
reciprocal square root transformation of
between
the sum of squared error and is a
calculated using equation of similarity was
measurement of the similarity in the
found to be 65.7. So, f2 value ensures
percent (%) dissolution between the two
sameness or equivalence of two curves.
50
dissolution
and
profiles
100.The
f2
are
value
Stability Study
Table 11: Stability Study of Optimized Formulation (F18) Carried out at 25 2oC/ 60
5 % RH
No. of
Disintegration
Wetting
Weeks
Time (sec)
Time(sec)
%Drug Content
Q10
(% Drug release in 10
min)
200.92
260.95
99.12 1.15
99.492.87
200.79
270.63
99.041.52
99.123.21
210.92
270.89
98. 951.32
98.563.18
220.98
270.73
98.651.21
98.122.59
220.83
290.79
98.441.29
97.393.26

Table 12: Stability Study of Optimized Formulation (F18) Carried out at 40 2oC/ 75
5 % RH
No. of
Disintegration
Wetting
%Drug
Q10
Weeks
Time (sec)
Time
Content
(% Drug release in 10
(sec)
min)
200.92
260.95
99.121.15
99.492.87
210.52
270.63
98.901.30
98.912.59
220.92
280.89
98.621.24
97.563.21
220.72
290.73
98.151.15
96.122.81
230.81
300.79
97.821.17
96.023.08

Stability study of ODT of Olanzapine was
the optimized formulation (F18) of ODT
carried out for 4 weeks at specified
revealed that no significant changes in the
condition. All data are mentioned in Table
physical parameters, disintegration time,
11 and Table 612. The stability studies of
wetting time, %drug content and % drug
54
release in 10
min when stored at
approach for rapid disintegrating tablet:
temperature and humidity conditions of 25
a review. Int J Pharma Res & Dev,
2oC/ 60 5 % RH and 40 2oC/ 75 5
3(3):17083.
% RH. So, we can say that formulation

having good stability.
2. Sharma, D., Kumar, D., Singh, M.,

Singh, G., Rathore, M. (2012). Fast
disintegrating tablets: a new era in
CONCLUSION
From the results obtained, it can be
novel drug delivery system and new
concluded that complex of Olanzapine
market opportunities. J Drug Del &
with cyclodextrin and PVP K 30
Therapeutics, 2(3):74-86.
markedly improved the solubility and
3. Tiwari, G., Pathak, A., Goyal, R.,
dissolution behaviour of Olanzapine. The 2
Jadaun, C., Shivhare, R., Sharma,
full factorial design applied in this study
K.(2012). Fast dissolving tablets: A
was used to provide details of the
novel approach to drug delivery. World
influence of independent variables on the
J of Pharma Res, 1(3):478-99.
responses. Thus concentration of CCS and
4. Thakur, R., Kashi, M. (2011). An
concentration of Kyron T 314 was selected
unlimited scope for novel formulations
as independent variable. From the results
as orally disintegrating systems: Present
of 2 full factorial designs revealed that
and future Prospects. J Applied Pharma
amount of CCS and amount of Kyron T
Sci, 1(1):13-19.
314 significantly affect the dependent
5. Limbachiya,
M.,
Agarwal,
M.,
variables, disintegration time and wetting
Sapariya, A., Soni, S. (2011). Solubility
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response surface design, an optimum point
water soluble drugs-a review. Int J
can be reached in the shortest time with
Pharma Res & Dev, 4(4):71-86.
minimum efforts. The derived polynomial

equation
predicting
and
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values
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Recent trends of fast dissolving tabletan overview of formulation technology.
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HOW TO CITE THIS ARTICLE

Chauhan, K., V., Kadliya, P., N., Patel, B., A., Patel, K., N., Patel, P., A. (2014). Formulation
Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility
Enhancement Technique Journal Club for Pharmaceutical Sciences (JCPS). 1(I), 33-57.
57

Formulation Optimization and Evaluation of Orodispersible Tablets of An Antipsychotic Drug Using Solubility Enhancement Technique

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ISSN No:2321 8630, V 1, I 1, 2014

Journal Club for Pharmaceutical Sciences (JCPS)

forms is Dysphagia or difficulty in

Introduction to Drug Delivery System

swallowing for many patients; however,

The oral route remains the preferred route

for administration of therapeutic agents.

underdeveloped muscular and nervous

One important drawback of such dosage

systems in young individuals, children and

in case of uncooperative patients, the

Copyright reserved by Journals Club & Co.

phenomenon. For example, a very elderly

patient can hide a conventional tablet

with dysphagia are not able to swallow

under his or her tongue to avoid its daily

conventional Olanzapine tablet.

dose of an atypical anti-psychotic. Orally

To overcome this problem an attempt was

disintegrating tablets (ODTs) are a perfect

fit for all these patients.

The Center for Drug Evaluation and

cyclodextrin was made to improve the

Research (CDER), US FDA defined Oral

aqueous solubility of Olanzapine and to

Disintegrating Tablets (ODT) as A solid

enhance dissolution rate of Olanzapine. It

may enhance the pregastric absorption of

lsubstances, which disintegrates rapidly,

Olanzapine. -cyclodextrin may act as

usually within a matter of seconds, when

channel forming agent because it helps in

placed upon the tongue.

quick disintegration of tablets and may act

Olanzapine is second generation atypical

as permeation enhancer to pass Olanzapine

thiobenzodiazepines. It is D2 and 5 HT2

prepared by using -cyclodextrin and four

receptor antagonist mainly used drug used

super disintegrants, namely as SSG,

in the treatment of schizophrenia and

croscarmellose sodium, crospovidone and

bipolar disorder. In this type of disease

Kyron T 314. Super disintegrants are

require rapid onset of action in order to

added to facilitate drug release and

control on mental condition.

consequently improve the solubility of

practically insoluble in water, having only

Olanzapine. Tablets were prepared by

using direct compression technique. The

undergoes extensive first pass metabolism.

simplicity and cost effectiveness of the

It has less extra pyramidal side effects

compared to other antipsychotics.Further,

Olanzapine has a small dose, optimum

alternative to granulation technologies.

molecular weight, unionized at salivary pH

MATERIALS & METHODS

hour).Some schizophrenic patients hide a

avoid its daily dose of an atypical

Olanzapine and other excipients were

antipsychotic. Also schizophrenic patients