formulation optimization and evaluation of orodispersible tablets of an antipsychotic drug using...

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]



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.,



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



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



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



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



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



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)



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



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



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



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



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



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 %



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 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



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



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 - - -



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



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


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


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



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


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


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



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



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


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


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



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.

formulation optimization and evaluation of orodispersible tablets of an antipsychotic drug using...

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