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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
©Copyright reserved by “Journals Club & Co.” 33
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
1Depatment 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 β-cyclodextrin (β-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 β-CD further enhanced solubility of drug compared to β-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, β-cyclodextrin, Croscarmellose sodium, Kyron T 314, Disintegration time, Wetting time, 32full factorial design INTRODUCTION
Introduction to Drug Delivery System
The oral route remains the preferred route
for administration of therapeutic agents.
One important drawback of such dosage
forms is “Dysphagia” or difficulty in
swallowing for many patients; however,
hand tremors, geriatric patients, the
underdeveloped muscular and nervous
systems in young individuals, children and
in case of uncooperative patients, the
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
*Address for Correspondence:
Krishna V. Chauhan, Department of Pharmaceutics, Shree Swaminarayan Sanskar Pharmacy College, Zundal, Gandhinagar, Gujarat, India. E-Mail Id: [email protected]
Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique
©Copyright reserved by “Journals Club & Co.” 34
patient can hide a conventional tablet
under his or her tongue to avoid its daily
dose of an atypical anti-psychotic. Orally
disintegrating tablets (ODTs) are a perfect
fit for all these patients.
The Center for Drug Evaluation and
Research (CDER), US FDA defined Oral
Disintegrating Tablets (ODT) as “A solid
dosage form containing medicina
lsubstances, which disintegrates rapidly,
usually within a matter of seconds, when
placed upon the tongue.
Olanzapine is second generation atypical
antipsychotic drug classified as a
thiobenzodiazepines. It is D2 and 5 HT2
receptor antagonist mainly used drug used
in the treatment of schizophrenia and
bipolar disorder. In this type of disease
require rapid onset of action in order to
control on mental condition. It is
practically insoluble in water, having only
60% oral bioavailability. Olanzapine
undergoes extensive first pass metabolism.
It has less extra pyramidal side effects
compared to other antipsychotics.Further,
Olanzapine has a small dose, optimum
molecular weight, unionized at salivary pH
and a long elimination half life (21-54
hour).Some schizophrenic patients hide a
conventional tablet under their tongue to
avoid its daily dose of an atypical
antipsychotic. Also schizophrenic patients
with dysphagia are not able to swallow
conventional Olanzapine tablet.
To overcome this problem an attempt was
made to formulate and evaluate
ODTsinclusion complex. Inclusion
complex of Olanzapine with β-
cyclodextrin was made to improve the
aqueous solubility of Olanzapine and to
enhance dissolution rate of Olanzapine. It
may enhance the pregastric absorption of
Olanzapine. β-cyclodextrin may act as
channel forming agent because it helps in
quick disintegration of tablets and may act
as permeation enhancer to pass Olanzapine
through oral mucosa. Tablets were
prepared by using β-cyclodextrin and four
super disintegrants, namely as SSG,
croscarmellose sodium, crospovidone and
Kyron T 314. Super disintegrants are
added to facilitate drug release and
consequently improve the solubility of
Olanzapine. Tablets were prepared by
using direct compression technique. The
simplicity and cost effectiveness of the
direct compression technique have
positioned direct compression as an
alternative to granulation technologies.
MATERIALS & METHODS Experimental Work
Materials
Olanzapine and other excipients were
gifted from West-Coast Pvt. Ltd.,
Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique
©Copyright reserved by “Journals Club & Co.” 35
Ahmedabad, Avicel pH 112 and Mannitol
SD 200 were gifted from Torrent Research
Centreand Kyron T 114 was gifted by
Corel Pharma Chem., Ahmadabad.
DRUG–EXCIPIENTS
COMPATIBILITY STUDY
Compatibility of the drug with excipients
was determined by FT-IR spectral
analysis, this study was carried out to
detect any changes on chemical
constitution of the drug after combined it
with the excipients. The samples were
taken for FT-IR study.
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 shaker. After complete
equilibration the supernatant solution were
collected carefully and filtered using
Whatman filter paper (No. 41) and
appropriately diluted. The OLP
concentration was determined using a UV
visible spectrophotometer in 226.8 nm.
Experiments were performed in triplicate.
The graph was plotted against drug
concentration vs. concentration of
betacyclodextrin. The blanks were
prepared using the same concentration of
betacyclodextrin with or without water
soluble polymer in distilled water so as to
cancel out any absorbance that may be
exhibited by betacyclodextrin.
Preparation of Inclusion Complex
Kneading Method
Required quantities of the Olanzapine and
β-CD were weighed to give 1:1, 1:2, 1:3
and 1:4 molar ratios and thoroughly mixed
with or without water soluble polymer. A
homogeneous paste of Olanzapine and β-
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 45-50°C. 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
Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique
©Copyright reserved by “Journals Club & Co.” 36
The Fourier transform infrared spectrum of
moisture free powdered sample of
Olanzapine, β-CD, PVP K 30 and kneaded
complex recorded on IR
spectrophotometer by potassium bromide
(KBr) pellet method.
Differential Scanning Calorimetry (DSC)
Analysis
DSC scans of the powdered samples were
recorded. The thermal traces were obtained
by heating the complex from 40 to 350 °C
at heating rate of 10 °C under inert
nitrogen dynamic atmosphere (100
ml/min) in open aluminium crucibles.
Drug Content Estimation 7
Olanzapine betacyclodextrin complex,
equivalent to 10 mg of drug, was weighed
accurately and added to 100 ml volumetric
flask. To this solution add small amount of
ethanol. These solutions were stirred for
60 mi, till the entire drug leached out then
make the volume up to mark with
phosphate buffer 6.8. Then this solution
was filtered. 0.5 ml of solution withdrawn
and added into 10 ml of volumetric flask
and volume was made to 10 ml (5 µm/ml)
with phosphate buffer pH 6.8. Drug
content was estimated by UV visible
spectrophotometer at 226.8 nm using
phosphate buffer pH 6.8 as blank.
Dissolution Study6, 7
Dissolution studies were carried out using
a USP dissolution apparatus type II with
900 ml dissolution mediums at 37 °C ± 0.5
and 50 rpm in Phosphate buffer (pH 6.8).
At fixed time intervals, 10 ml aliquots
were withdrawn, filtered, suitably diluted
and then assayed for Olanzapine content
by measuring the absorbance at 226.8 nm.
Fresh media (10 ml), which was pre-
warmed at 37 °C, was replaced in to the
dissolution medium after each sampling to
maintain its constant volume throughout
the test. Dissolution studies were
performed in three replicates (n = 3), and
calculated mean values of cumulative drug
release were used while plotting the
release curves.
Saturation Solubility Study
Saturation solubility study was performed
according to method reported by Higuchi
and Connors. Excess quantities of
inclusion complex were added to 25 mL
distilled water in glass stoppered conical
flasks and shaken for 24 h in rotary flask
shaker. After shaking the solutions were
filtered through Whatman filter paper No.
41. The filtrate was analyzed
spectrophotometrically at 226.8 nm. Each
sample was done in triplicate.
Formulation and Evaluation of Tablets
Selection of super disintegrant
In preliminary trial batches, different
concentrations i.e. 2 and 4% of Sodium
starch glycolate (SSG), Crospovidone
(CP), Croscarmellose sodium (CCS) and
Kyron T 314 were screened. From the all
Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique
©Copyright reserved by “Journals Club & Co.” 37
the four super disintigrants CCS and
Kyron T 314 had shown less disintegration
time and wetting time compared to SSG
and CP.
Method - Direct Compression Method
According to the formula given in table1
all the ingredients (without magnesium
stearate and aerosil) were passed through
#40 mesh separately. Required quantity of
each excipient was weighed accurately and
blend was mixed thourouly. Lubricants i.e.
aerosil and magnesium stearate were
passed through 80# and mixed them to
above blend. Powder blend was
compressed using 9 mm concave punch on
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
physicochemical properties of blends.
There are many formulation and process
variables involved in mixing and all these
can affect the characteristics of blends
produced. The various characteristics of
blends tested are as given below.
Bulk density
Apparent bulk density was determined by
pouring 10 gm of powder blend into
graduated cylinder and measuring the
volume.
Bulk density =Weight of the powder /
Volume of the packing
Tapped Density
Weighed quantity of powder blend was
taken into a graduated cylinder and volume
occupied by powder blend was noted
down. Then cylinder was subjected to 500,
750 and 1250 taps in tap density tester
According to USP the blend was subjected
to 500 taps. The %volume variation was
calculated and subjected for additional 750
taps and %volume variation is calculated.
Tapped density= Weight of the powder /
volume of the tapped packing
Carr’s compressibility index
The compressibility index of the blends
will be determined by Carr’s
compressibility index.
Carr’s compressibility index (%) =
Carr’s compressibility index (%) =
Tapped density-Bulk density X 100
Tapped density
Hausner's ratio
Hausner's ratio is an index of ease of
powder flow. It is calculated by following
formula.
Hausner's ratio = Tapped density / Bulk
density
Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique
©Copyright reserved by “Journals Club & Co.” 38
Angle of repose
Angle of repose (θ) is a measure of
flowability of material. It was determined
using fixed height funnel method. A glass
funnel was placed with its tip positioned at
a fixed height (h) above a graph paper on a
horizontal surface. The blend was poured
through a funnel until the apex of conical
pile touched the tip of the funnel. The
radius of the pile (r) was measured and
angle of repose was calculated as follows.
θ = tan-1 (h/r)
Where, θ = angle of repose
h = height of the pile
r = average radius of the powder cone
Evaluation of Tablets
Thickness
The thickness of the tablets was
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
weight tablets were being made. Twenty
tablets were selected randomly from each
formulation, weighed individually and the
average weight and % variation of weight
was calculated.
Disintegration Time
The USP device to test disintegration has
six glass tubes that are “3 long, open at the
top, and held against 10” screen at the
bottom end of the basket rack assembly.
One tablet is placed in each tube and the
basket rack is poisoned in 1 liter beaker of
distilled water at 37± 2 °C, such that the
tablets remain below the surface of the
liquid on their upward movement and
descend not closer than 2.5cm from the
bottom of the beaker. The time required to
obtain complete disintegration of all the
tablets will be noted.
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
Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique
©Copyright reserved by “Journals Club & Co.” 39
ethanol. The washing obtained was added
to initial filtrate and volume was made up
to 100 ml with ethanol. From above
solution 0.5 ml of stock solution was
diluted to 100 ml of phosphate buffer pH
6.8. The drug content was determined
spectrophotometrically at 226.8 nm.
Dissolution Studies 7
Dissolution studies were carried out for all
the formulation combinations in triplicate,
employing USP XXIII paddle method
(Apparatus 2) using phosphate buffer pH
6.8, as the dissolution medium (900 ml) at
50 rpm and 37 ± 0.5ºC. An aliquot of
sample was periodically withdrawn at
suitable time intervals and volume
replaced with equivalent amounts of plane
dissolution medium. The samples were
analyzed spectrophotometrically at 226.8
nm.
Full Factorial Design
A 32 Factorial design was chosen for the
current formulation optimization study. In
this design two factors were evaluated,
each at 3 levels, and experimental trials
were performed at all 9 possible
combination. In the preliminary trial runs,
5 % Cross carmalose sodium and 4 % of
Kyron T 314 showed good results. So
these levels were selected and subjected to
further optimization. Cross carmalose
sodium and Kyron T 314were selected as
independent factors whereas disintegration
time (DT) and wetting time (WT) were
measured as responses. The polynomial
equation can be used to draw conclusions
after considering the magnitude of
coefficient and the mathematical sign. The
responses were analyzed for ANOVA
using Design Expert version 8.0.5. A
mathematical equation was generated for
each response parameter. The
mathematical models were tested for
significance. Response surface plots were
generated for each response to study the
behaviour of the system.
Table 1: Selection of Levels for Independent Variables and Coding of Variable
Levels
Coded value
INDEPENDENT VARIABLES
X1 (%) X2 (%)
Low -1 1 0
Intermediate 0 3 2
High 1 5 4
Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique
©Copyright reserved by “Journals Club & Co.” 40
Table 2: Factorial Design Layout and Data Transformation for Factorial Batches
Run Independent
Variables in
coded form
Independent Variable in
actual form
Dependent variable
Factor
1
Factor
2
Cross
carmalose
sodium
Kyron T
314
Disintegration
Time (Sec.)
Wetting
Time (Sec.)
1 -1 -1 1 0 480.35 540.52
2 -1 0 1 2 330.42 390.56
3 -1 1 1 4 290.39 350.43
4 0 -1 3 0 410.45 490.49
5 0 0 3 2 280.58 330.39
6 0 1 3 4 240.65 300.32
7 1 -1 5 0 340.43 400.46
8 1 0 5 2 230.59 290.39
9 1 1 5 4 190.52 250.78
Table 3: Formulations using 32Factorial Design
FORMULATION
INGREDIENTS
F1 F2 F3 F4 F5 F6 F7 F8 F9
Olanzapine -β-CD –PVP K
30 complex
130.
88
130.
88
130.
88
130.
88
130.
88
130.
88
130.
88
130.
88
130.
88
Croscarmellose sodium 2.5 2.5 2.5 7.5 7.5 7.5 12.5 12.5 12.5
Kyron T 314 0 5 10 0 5 10 0 5 10
Microcrystalline cellulose
pH 112
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.
62
56.
62
51.
62
56.
62
51.
62
46.
12
51.
62
46.
62
41.
62
Total Weight 250(mg/tablet)
Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique
©Copyright reserved by “Journals Club & Co.” 41
Validation of statistical model
From overlay plot of responses, optimized
formulation was selected as checkpoint to
validate RSM. The tablets were formulated
using chosen optimal composition &
evaluated for DT & WT.
Table 4: Composition of Optimized Formulation
FORMULATION INGREDIENTS F10
Olanzapine-β-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
Stability study was carried out for the
optimized formulation for 25 ± 2oC/ 60 ± 5
% RH and 40 ± 2oC/ 75 ± 5 % RH for 1
months and samples were withdrawn at the
end of 0, 1, 2, 3 and 4 week and evaluated
for active drug content, disintegration
time, wetting time and Invitro drug release.
Comparison of Optimized Formulation
with Market Product Using Similarity
Factor (f2)
The similarity factor (f2) given by SUPAC
guidelines for modified release dosage
form was used as a basis to compare
dissolution profile. The dissolution profiles
are considered to be similar when f2 is
between 50 and 100. The dissolution
profiles of products were compared
following formula,
n
f2 = 50 x log {[1+(1/n) Σ | Rj – Tj | 2 ] -
0.5 x 100}
j=1
Where,
n = number of time points
Rj = Dissolution value of the reference
batch at
time t
Tj = Dissolution value of the test batch at
time t.
RESULT AND DISCUSSION
Identification of Drug by FT - IR
Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique
©Copyright reserved by “Journals Club & Co.” 42
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
E – Drug + Kyron T 314
B - Drug + Crosspovidone
F – Drug+ MCC pH 112
C – Drug + Croscarmellose sodium
G – Drug + Mannitol SD 200
Interpretation
To study the compatibility of drug with
excipients IR spectra of drug in
combination with excipients in 1:1 ratio
was studied prior to preparation of
Olanzapine orally disintegrating tablets.
FTIR spectra of Olanzapine show
characteristic bands are attributed to the
stretching of different group vibrations:
3247.27 cm-1 stretching of the N-H band
2930.2 cm-1 stretching of the N-H band
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
benzene
The IR spectrums of Olanzapine and its
combination with crospovidone,
croscarmellose, etc. were shown in Figures
2 indicate that there was no
Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique
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physicochemical interaction in between
drug and studied excipients because all
characteristics bands were presented in
physical mixture.
Phase Solubility Study
Fig 3: Phase Solubility of Olanzapine
From the Phase solubility analysis it was
concluded that as the concentration of
betacyclodextrin increased concentration
of Olanzapine is also increased. According
to Higuchi and Connors, the obtained
curve was AL type of solubility curve.
Addition of the water soluble polymer like
PVP K 30 and PEG 4000 with
betacyclodextrin solubility of the drug was
further increased. The stability constant
was found to be 122.19, 128.77 and 144.93
for β-CD, β-CD with PEG 4000 and β-CD
with PVP K 30 respectively. From the
graph it was concluded that solubility of
the drug higher in case of PVP K 30
compare to PEG 4000. So PVP K 30 was
selected for the preparation of the
complex.
Characterization of Olanzapine-β-
cyclodextrin-PVP K 30 Complex
Drug Content Estimation
The drug content of inclusion complex
prepared by kneading was found 94.44
%±1.25to 97.25 % ±1.10.
Saturation Solubility Study
In the present work, enhancement in the
solubility was observed in case of
inclusion complex. Solubility of pure
Olanzapine was found to be 0.0343±2.45
mg/mL and solubility of complex was
found to be 0.0765±3.36mg/mL.
Fourier Transformation Infrared
Spectroscopy
IR is a highly sensitive method of analysis,
all spectra of complex showed some or
other changes from parent spectra (Figure
3). 3247.27 cm-1 stretching of the N-H
y = 0.172x + 0.0017R² = 0.9926
y = 0.2069x + 0.0018R² = 0.9608
y = 0.1796x + 0.0017R² = 0.977
00.0005
0.0010.0015
0.0020.0025
0.0030.0035
0.004
0 0.002 0.004 0.006 0.008 0.01
Conc
. of O
lanz
apin
e(m
g/m
l)
Concentration of β -CD(mg/ml)
β-CD
β-CD with PVP K 30
β-CD with PEG 4000
Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique
©Copyright reserved by “Journals Club & Co.” 44
band, 2930.2 cm-1 stretching of the N-H
band, 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 benzene.
In the FTIR spectra of prepared
complexes, Olanzapine bands are almost
completely obscured by very intense and
broad CD bands, which are hardly
influenced by complex formation.
Absorption band at 3247.27 cm-1 is
completely disappeared in the complex
spectra, which indicate that hydrogen bond
formation between hydroxyl group of
betacyclodextrin, PVP K 30 and amine
group of the drug. Reduction in intensity
of the C=C band at 1586.16 cm-1.
Fig 4: FTIR Spectra of (a) Drug (b) β-CD (c) PVP K 30 (d) Physical mixture and (e)
Complex
Differential Scanning Calorimetry
Olanzapine exhibited a characteristic
endothermic peak at 196.50°C,
corresponding to the Olanzapine melting
point and indicating that the drug is in a
crystal polymorphic form. Furthermore, β-
CD and PVP K 30 showed broad
endothermic events in the range from 80 to
130 °C, which are related to evaporation of
water from the cyclodextrin. β-CD also
shows small endo or exo effects at 297–
320 °C due to thermal degradation. In
DSC thermogram of Olanzapine-β CD-
PVP K 30 Complex peak were disappeared
which gave conformation of complex
Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique
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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-β-CD
Complex
Dissolution Study of Olanzapine and its
Inclusion Complex
Based on the % CDR 1:3 M of the drug to
betacyclodextrin was shown higher % drug
release compare to other molar ratios. So it
was selected for the further preparation of
complex with PVP K 30.
0102030405060708090
100
0 10 20 30 40 50 60
% C
DR
Time (mins.)
drug
1:1 M
1:2 M
1:3 M
1:4 M
Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique
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Fig 6: Comparative Dissolution Profiles of Various Molar Ratios of Olanzapine-β-CD-
PVP K 30
Based on % drug release from different
molar ratios of complex Olanzapine: β-
cyclodextrin, 1:3 molar ratio with 10 %
PVP K 30 was selected as optimized ratio
as it was shown 99.31 % drug release in 30
min as compared to 1:3 with 5 % PVP K
30 molar ratio that was shown 99.50 %
release at the end of 60 min. 1:3 molar
ratio with 15 % PVP K 30was not shown
significant increase in% drug release when
compare to 1:3 molar ratio with 10 % PVP
K 30. So, 1:3 molar ratio with 10 % PVP
K 30 was optimized. The increase in the
dissolution of Olanzapine with β-CD and
PVP K 30 could be explained by the
principal of hydrophilicity, inclusion
complex formation and the amorphous
form generation of Olanzapine. The high
solubility of β-CD and PVP K 30 in water
resulted in better wettability of drug
particles and local enhancement of its
solubility at the diffusion layer
surrounding the drug particles.
Table 5: Pre-Compression Evaluation Parameters of Powder Blend of Factorial Batches
Batch Code Bulk Density (gm/ml)
Tapped Density (gm/ml)
Carr’s index (%)
Angle of repose
( °)
Hausner’s ratio
F1 0.441±0.032 0.495±0.038 13.20±0.32 27.3°±0.21 1.13±0.29 F2 0.482±0.025 0.552±0.019 12.72±0.13 29.4°±0.22 1.14±0.19 F3 0.490±0.017 0.560±0.029 13.50±0.15 28.7°±0.13 1.14±0.16 F4 0.475±0.018 0.539±0.09 12.32±0.29 27.6°±0.22 1.12±0.14 F5 0.480±0.010 0.565±0.015 14.28±0.32 26.4°±030 1.16±0.25 F6 0.492±0.013 0.554±0.023 12.91±0.19 27.8°±0.18 1.12±0.20 F7 0.503±0.017 0.576±0.010 12.40±0.19 27.1°±0.25 1.14±0.16 F8 0.469±0.029 0.537±0.016 13.20±0.15 26.2°±0.22 1.15±0.13 F9 0.476±0.019 0.529±0.024 12.82±0.09 27.3°±0.15 1.12±0.10
All values are expressed as mean ± standard deviation, n=3
0
20
40
60
80
100
0 10 20 30 40 50 60
% C
DR
Time (mins.)
1:3 M
PVP K 30 - 5%
PVP K 30 - 10%
PVP K 30 - 15 %
Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique
©Copyright reserved by “Journals Club & Co.” 47
Evaluation of Powder bland
The powder blend for all nine formulations
were evaluated for bulk density which
ranged from 0.441 to 0.503, tapped density
which ranged from 0.529 to 0.576, Carr’s
index ranged from 12.32 to 14.28,
Hausner’s ratio ranged from 1.12 to 1.16
and angle of repose ranged from 26.2 to
29.4 °. All these results indicate that, the
power blend possess good flowability and
compressibility properties. Hence, tablets
were prepared using direct compression
method.
Evaluation of Tablets
Table 6: Physical Evaluation Parameters of Tablets of factorial batches
Batch
Code
Weight
Variation
(mg)±SD,
n=20
Hardness
(kg/cm2)
±SD
Thickness
(mm) ±SD
Friability
(%)±SD
Drug Content
(%)± SD
F1 Pass 3.2 0.23 4.95±0.02 0.48±0.02 99.48±1.15
F2 Pass 3.5 0.52 4.93 ±0.03 0.42±0.01 99.21±1.23
F3 Pass 3.4 0.29 4.95±0.02 0.37±0.04 99.67±1.73
F4 Pass 3.1 0.52 4.93±0.04 0.56±0.03 98.32±1.33
F5 Pass 3.5 0.59 4.97±0.01 0.49±0.01 98.53±1.39
F6 Pass 3.3 0.26 4.95±0.03 0.41±0.03 98.56±1.20
F7 Pass 3.5 0.52 5.15±0.02 0.39±0.02 99.14±1.31
F8 Pass 3.1 0.53 4.95±0.01 0.34±0.01 99.78±1.30
F9 Pass 3.2 0.28 4.93±0.02 0.46±0.03 98.23±1.14
All values are expressed as mean ± standard deviation, n=3
All the tablet preparations were evaluated
for various physical parameters before
proceeding further. Table 6 includes the
values (mean SD) of weight variation,
hardness, thickness and friability of eight
tablet batches prepared using different
combinations of functional excipients. All
the eight batches passed weight variation
test. All the formulated (F9 to F17) tablets
passed weight variation test as the %
weight variation was within the
pharmacopoeial limits of 5% of the
weight. The weights of all the tablets were
found to be uniform with low standard
deviation values.
Thickness of all tablets was in the range
between 4.93 mm to 5.15 mm. Hardness of
tablets was in range between 3.1 to 3.5
kg/cm2.Friability was in range between
0.34 to 0.56 %. Thus, all the physical
Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique
©Copyright reserved by “Journals Club & Co.” 48
parameters of the manually compressed
tablets were quite within control. Friability
values were less than 1 % in all cases
shows good mechanical strength at the
time of handling and transports.
The % drug content for tablets of all
formulation was found to be in the range
of 98.23 to 99.67%. Thus the assay of
Olanzapine was found to be quite within
the range.
The results shown in Table 2indicated that
concentration-dependent disintegration
was observed in batches prepared using
combination of CCS and Kyron T 314. As
CCS combined with Kyron T 314, by
keeping concentration of CCS constant
and increase concentration of Kyron T 314
from 0 to 4%, disintegration time was
decreased as shown in result.
The wetting time of tablets as shown in
Table 2 of all nine formulations was in the
range of 26 to 54 seconds. The wetting
time is closely related to the disintegration
time.
Fig 7: Effect of Super disintegrants on Dissolution Profiles of Factorial Batches
(F1-F9)
The dissolution profiles of all the nine
formulations are shown in Figure 6.17.
From graph it was concluded that as the
concentration of super disintegrant
increases, % drug release was also
increased. % drug release from F8 and F9
formulations prepared with CCS 5 % and
3% and4 % Kyron T 314 was shown 94.52
and 99.09 % in 10 minutes. Combination
of two disintegrates also improves
dissolution rate as compared to individual
super disintegrant. The release of drug was
largely depended on the disintegration
0
10
20
30
40
50
60
70
80
90
100
0 5 10 15 20 25 30
% C
DR
Time(mins.)
F1
F2
F3
F4
F5
F6
F7
F8
F9
Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique
©Copyright reserved by “Journals Club & Co.” 49
time. That is faster the disintegration of
tablets, better and faster is the release.
Factorial equation for Dependent
Variables
1) Factorial equation for Disintegration
Time
Y= 27.89 – 5.50 X1 -8.33X2 +1.25X1X2 -
0.17 X12 + 4.67 X2
2, R2= 0.9940
Positive sign in front of terms indicate
synergistic effect while negative indicate
antagonistic effect upon responses.So, sign
of b1 andb2 were negative shows that as a
concentration of CCS and Kyron T 314
increases , DT decreases. As the R2 value
nearer to 1 indicate selected model was
significant.
2) Factorial equation for Wetting Time
Y= 33.11 -5.67 X1 -8.67 X2 +1.25 X1X2
– 0.67X2 + 6.33 X22, R2= 0.9965
Positive sign in front of terms indicate
synergistic effecy while negative indicate
antagonistic effect upon responses. So,
sign of b1 andb2 were negative shows that
as a concentration of CCS and Kyron T
314 increases ,WT decreases. As the R2
value nearer to 1 indicate selected model
was significant.
ANOVA for Quadratic Model for DT and
WT
ANOVA table used to generate
mathematical models. The high values of
correlation coefficient for DT and WT
indicate a good fit i.e.good agreement
between the dependent and independent
variables. The mathematical model was
evolved by omitting insignificant term (p
>0.05). So, the main effect X1 & X2 were
found significant as p value was < 0.05.
Table 7: ANOVA Response Surface Quadratic Model for Disintegration Time
Source SS df MS F Value p-value
prob > F R2
Model 648.03 5 129.61 451.53 0.0002
0.9987
A –CCS 181.50 1 181.50 632.32 0.0001
B-Kyron T 314 416.67 1 416.67 1451.61 <0.0001
AB 6.25 1 6.25 21.77 0.0186
A2 0.056 1 0.056 0.19 0.6897
B2 43.56 1 43.56 151.74 0.0012
Cor Total 648.89 8 - - -
Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique
©Copyright reserved by “Journals Club & Co.” 50
Table 8: ANOVA Response Surface Quadratic Model for Wetting Time
Source SS df MS F
Value
p-value
prob > F R2
Model 730.69 5 146.14 199.78 0.0006
0.9970
A - CCS 192.67 1 192.67 263.39 0.00057
B-Dilution ratio 450.67 1 450.67 616.10 0.0007
AB 6.25 1 6.25 8.54 0.0613
A2 0.89 1 0.89 1.22 0.3508
B2 80.22 1 80.22 109.67 0.0019
Cor Total 732.89 8 - - -
ANOVA Table shows the results of the
analysis of variance (ANOVA), which was
used to generate mathematical models. The
high values of correlation coefficient for
DT and WT indicate a good fit i.e. good
agreement between the dependent and
independent variables. The F value in the
ANOVA table is the ratio of model mean
square (MS) to the appropriate error (i.e.
residual) mean square. The mathematical
model was evolved by omitting
insignificant term (p > 0.05). So, the main
effect X1 & X2 were found significant as p
value was < 0.05.
Response Surface Plots
Effect of X1 and X2 on Disintegration
Time
Fig 8: Two-Dimensional Contour Curve for Disintegration Time
Design-Expert® SoftwareFactor Coding: ActualDT
Design Points48
20
X1 = A: CCSX2 = B: Kyron T 314
1.00 2.00 3.00 4.00 5.00
0.00
1.00
2.00
3.00
4.00DT
A: CCS
B: K
yron
T 3
14
30
40
Prediction 21.024
Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique
©Copyright reserved by “Journals Club & Co.” 51
Fig 9: 3-D graph showing effect of CCS and Kyron T 314 on Disintegration Time (R1)
This contour plot shows the effect of
concentration of croscarmellose (X1) and
concentration of kyron T 314 on
disintegration time (Y1). As concentration
of X1 and X2 increases, the value of
response Y1 decreases.
Effect of X1 and X2 on Wetting Time
Fig 10 : Two-Dimensional Contour Curve for Wetting Time
Design-Expert® SoftwareFactor Coding: ActualDT
Des ign points above predicted valueDes ign points below predicted value48
20
X1 = A: CCSX2 = B: Kyron T 314
0.00
1.00
2.00
3.00
4.00
1.00
2.00
3.00
4.00
5.0010
20
30
40
50
DT
A: CCS
B: Kyron T 314
21.02421.024
Design-Expert® SoftwareFactor Coding: ActualWT
Des ign Points54
26
X1 = A: CCSX2 = B: Kyron T 314
1.00 2.00 3.00 4.00 5.00
0.00
1.00
2.00
3.00
4.00WT
A: CCS
B: K
yron
T 3
14 30
40
50
Prediction 26.636
Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique
©Copyright reserved by “Journals Club & Co.” 52
Fig 11 : 3-D graph showing effect of CCS and Kyron T 314 on Wetting Time (R1)
This contour plot shows the effect of
concentration of croscarmellose (X1) and
concentration of kyron T 314 on wetting
time (Y2). As concentration of X1 and X2
increases, the value of response Y2
decreases.
Fig 12 : Overlay Plot of Response Variables
From overlay plot of responses, optimized
formulation was selected as checkpoint to
validate RSM. The Overlay plot of
responses generates an optimized area as
per desired criteria of DT should be 20 sec
& WT should be 25 sec. So, it can be
concluded that by adopting systemic
formulation approach one can reach to an
optimum point in shortest time with
minimum effect. Thus, we can conclude
that statistical model is mathematically
valid.
Design-Expert® SoftwareFactor Coding: ActualWT
Des ign points above predicted valueDes ign points below predicted value54
26
X1 = A: CCSX2 = B: Kyron T 314
0.00
1.00
2.00
3.00
4.00
1.00
2.00
3.00
4.00
5.0020
30
40
50
60
WT
A: CCS B: Kyron T 314
26.63626.636
Design-Expert® SoftwareFactor Coding: ActualOverlay Plot
DTWT
Design Points
X1 = A: CCSX2 = B: Kyron T 314
1.00 2.00 3.00 4.00 5.00
0.00
1.00
2.00
3.00
4.00Overlay Plot
A: CCS
B: K
yron
T 3
14
DT: 30.000
WT: 26.000
WT: 35.000
DT: 21.024WT: 26.636X1 4.47X2 3.73
Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique
©Copyright reserved by “Journals Club & Co.” 53
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)
Carr’s compressibility index (%) Carr’s 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) 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) 3.5±0.23 4.0±0.35
Disintegration time (sec) 24±0.75 20±0.92
Wetting time (sec) 29±0.89 26±0.95
Q10(% Drug release in 10 min) 98.89±3.12 99.49±2.87
Fig 13: Comparative Release Profile between Marketed Formulation and Optimized
Batch (F10)
0
20
40
60
80
100
0 2 4 6 8 10
% D
rug
rele
ase
Time (mins)
Optimized Batch
Marketed Product
Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique
©Copyright reserved by “Journals Club & Co.” 54
Similarity Factor
The similarity factor (f2) is a logarithmic
reciprocal square root transformation of
the sum of squared error and is a
measurement of the similarity in the
percent (%) dissolution between the two
curves. The dissolution profiles are
considered to be similar when f2 is
between 50 and 100.The f2 value
calculated using equation of similarity was
found to be 65.7. So, f2 value ensures
sameness or equivalence of two curves.
Stability Study
Table 11: Stability Study of Optimized Formulation (F18) Carried out at 25 ± 2oC/ 60 ±
5 % RH
No. of
Weeks
Disintegration
Time (sec)
Wetting
Time(sec)
%Drug Content Q10
(% Drug release in 10
min)
0 20±0.92 26±0.95 99.12± 1.15 99.49±2.87
1 20±0.79 27±0.63 99.04±1.52 99.12±3.21
2 21±0.92 27±0.89 98. 95±1.32 98.56±3.18
3 22±0.98 27±0.73 98.65±1.21 98.12±2.59
4 22±0.83 29±0.79 98.44±1.29 97.39±3.26
All values are expressed as mean ± standard deviation, n=3
Table 12: Stability Study of Optimized Formulation (F18) Carried out at 40 ± 2oC/ 75 ±
5 % RH
No. of
Weeks
Disintegration
Time (sec)
Wetting
Time
(sec)
%Drug
Content
Q10
(% Drug release in 10
min)
0 20±0.92 26±0.95 99.12±1.15 99.49±2.87
1 21±0.52 27±0.63 98.90±1.30 98.91±2.59
2 22±0.92 28±0.89 98.62±1.24 97.56±3.21
3 22±0.72 29±0.73 98.15±1.15 96.12±2.81
4 23±0.81 30±0.79 97.82±1.17 96.02±3.08
All values are expressed as mean ± standard deviation, n=3
Stability study of ODT of Olanzapine was
carried out for 4 weeks at specified
condition. All data are mentioned in Table
11 and Table 612. The stability studies of
the optimized formulation (F18) of ODT
revealed that no significant changes in the
physical parameters, disintegration time,
wetting time, %drug content and % drug
Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique
©Copyright reserved by “Journals Club & Co.” 55
release in 10 min when stored at
temperature and humidity conditions of 25
± 2oC/ 60 ± 5 % RH and 40 ± 2oC/ 75 ± 5
% RH. So, we can say that formulation
having good stability.
CONCLUSION From the results obtained, it can be
concluded that complex of Olanzapine
with ß cyclodextrin and PVP K 30
markedly improved the solubility and
dissolution behaviour of Olanzapine. The 2
full factorial design applied in this study
was used to provide details of the
influence of independent variables on the
responses. Thus concentration of CCS and
concentration of Kyron T 314 was selected
as independent variable. From the results
of 2 full factorial designs revealed that
amount of CCS and amount of Kyron T
314 significantly affect the dependent
variables, disintegration time and wetting
time. It is thus concluded that by using
response surface design, an optimum point
can be reached in the shortest time with
minimum efforts. The derived polynomial
equation and contour plots aid in
predicting the values of selected
independent variables for the preparation
of optimum Olanzapine Orodispersible
tablets with desired properties.
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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.