international standard serial number (issn): 2319-8141 .... rpa131400180.pdf · mt /m∞ = k tn [4]...

International Standard Serial Number (ISSN): 2319-8141 International Journal of Universal Pharmacy and Bio Sciences 2(5): September-October 2013

INTERNATIONAL JOURNAL OF UNIVERSAL

PHARMACY AND BIO SCIENCES IMPACT FACTOR 1.89***

ICV 3.00*** Pharmaceutical Sciences RESEARCH ARTICLE……!!!

Received: 31-08-2013; Accepted: 03-09-2013

pH INDEPENDENT SUSTAINED RELEASE SWELLABLE MATRIX TABLET OF

QUETIAPINE FUMARATE

Harale Poonam*, Dr Ashwini Madgulkar, Mrs. P. M. Chaudhari

Pad Dr. D. Y. Patil College of Pharmacy, Akurdi, Pune-411044.

KEYWORDS:

Quetiapine fumarate, pH-

independent release,

HPMC matrices. Organic

acids.

For Correspondence:

Harale Poonam*

Address:

Pad Dr. D. Y. Patil

College of Pharmacy,

Akurdi, Pune-411044.

Email-

[email protected]

m.

Mob. No- 8237327152

ABSTRACT

Psychosis is a mental illness of severe type in which the patient loses

touch with reality. Quetiapine fumarate is the most recently

introduced atypical antipsychotic. Quetiapine Fumarate is weakly

basic drugs and their salts shows pH-dependent solubility that may

show release problems from sustained release dosage forms at higher

pH of small intestine. This might decrease drug bioavailability and

cause variable oral absorption. Three types of organic acids namely

tartaric, citric and succinic acid in the concentrations of 10, 20 and

30 mg were added to the matrices prepared by hydroxypropyl

methylcellulose (HPMC K4M) and dicalcium phosphate. The

addition of pH adjusters such as organic acids increases the

permeability of the dosage form. Organic acids create a suitable

microenvoirmental pH and result in advanced drug solubility at high

pH. The drug release studies were carried out at pH 1.2 and pH 6.8

separately and similarity factor (ƒ2) were calculated. It was found

that incorporation of 35mg tartaric acid in tablet formulations with

40mg HPMC resulted in a suitable pH-independent release profiles

with significant higher ƒ2 value (83.6) compared to acid free tablet.

The other two acids did not show the desirable effects. It seems that

lower pKa of tartaric acid accompanied by its higher solubility were

the main factors in the achievement of pH-independent release

profiles. In this study it was observed that the release characteristics

of the formulation are attributed mainly due to organic acid and

polymer concentration.

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International Standard Serial Number (ISSN): 2319-8141

INTRODUCTION:

Many drugs (e.g. weakly acidic and basic drugs) demonstrate pH dependent solubility in the pH

range of the gastrointestinal tract. The rate at which a drug goes into the solution when it is dissolved

in a medium is proportional to the solubility of the drug in medium. Hence, pH dependent solubility

in the pH range of the gastrointestinal tract lead to different dissolution rates in the different parts of

the gastrointestinal tract. pH dependent drug release from controlled release dosage form drugs (e.g.

weakly acidic and basic drugs) demonstrate pH dependent solubility in the pH range of the

gastrointestinal tract. The rate at which a drug goes into the solution when it is dissolved in a

medium is proportional to the solubility of the drug in medium. Hence, pH dependent solubility in

the pH range of the gastrointestinal tract lead to different dissolution rates in the different parts of

the gastrointestinal tract. pH dependent drug release from controlled release dosage form could

result in reduced and variable bioavailability [3]. Several articles have been published on different

approaches to overcome the problem of pH dependent drug release from controlled release dosage

forms. Most of the approaches for pH independent drug delivery of weakly acidic or weakly basic

drugs are based on presence of buffer systems or organic acids within the drug formulation [4-11].

The most commonly used method of modifying drug release is to include it in matrix system [12].

Hydrophilic polymer matrix system are widely used for designing oral controlled drug delivery

dosage forms because of their flexibility to provide a desirable drug release profile, cost

effectiveness and broad regulatory acceptance.

Quetiapine Fumarate (QF) is an atypical psychotropic agent of dibenzothiazepine class. It is used for

the treatment of acute manic episodes associated with bipolar I disorder and treatment of

schizophrenia. It has mean elimination half-life about 6 hours so it is administered twice or thrice a

day to maintain therapeutic plasma level [18]. Once a day controlled release formulation of

Quetiapine may improve patient compliance and clinical efficacy of treatment. Quetiapine shows pH

dependent solubility i.e. it is soluble in acidic aqueous media but solubility of drug decreases with

increase in pH of media, which can result in pH dependent release of drug from drug delivery

system. The objective of present study was to develop once a day matrix tablet formulation for pH

independent drug release from the system throughout the gastrointestinal tract It should be suitable

for drugs having pH dependent solubility i.e. highly soluble in acidic pH and less soluble in alkaline

pH.

The objective of this study to achieve a pH independent release of a weakly basic drug from matrix

tablet consisting of HPMC K4M polymer and organic acid like tartaric acid, citric acid and succinic

acid.




MATERIALS AND METHODS

Materials

Quetiapine fumarate was obtained as a gift sample from Aurbindo Pharmaceuticals, Hyderabad.

HPMC K4M was obtained from Signet Chemical corporation, Mumbai. Tartaric Acid, citric acid

and succinic acid was obtained from S.D. Fine Chem Industries, Mumbai. All other chemicals used

were of analytical grade.

Solubility of Quetiapine Fumarate: The solubility of the drug was carried out in water, 0.1N HCl

and in different phosphate buffer. The excess amount of drug was dissolved in 1 ml of solvent. The

solution was then subjected to ultrasonication for 30 minutes. It was then allowed to stand for 24 hr

at RT (room temperature) in tightly closed vials to attain saturation equilibrium. After 24 hours the

solution was filtered through whatman filter paper no. 41. It was then diluted appropriately with the

solvent and its absorption was observed through UV spectrophotometer at 290 nm [5, 6].

Formulation of tablet: Different tablet formulations were prepared by direct compression method.

Quetiapine fumarate, HPMC K4M and dicalcium phosphate were passed from sieve of # 40 and

mixed for 10 min. Organic acid was then passed through sieve of # 60 added to the above mixture.

Magnesium stearate was passed through sieve of # 60 and added to the above mixture. The whole

bulk of powder was then mixed thoroughly for 15 min. The powder was then compressed into round

shaped tablets on Multi-station tablet press (10mm diameter). Characteristic of the blend such as

bulk density, compressibility index and angle of repose were determined for each formulation [6, 7].

Formulation Batches: The formulation batch F0 was prepared without adding organic acid,

formulation batches from T1 to T5, C1 to C2 and S1 to S5 were taken with HPMC K4M and tartaric

acid, citric acid, succinic acid at various concentrations.

Table No. 1: Formulation Batches from F0 to S5

Formulations Quetiapine

fumarate

HPMC

K4M

Dicalcium

phosphate

Tartaric

acid

Citric

acid

Succinic

acid

Magnesium

stearate

F0 200 60 74 - - - 1

T1 200 60 64 10 - - 1

T2 200 55 69 10 - - 1

T3 200 60 54 20 - - 1

T4 200 50 64 20 - - 1

T5 200 60 44 30 - - 1

T6 200 45 59 30 - - 1

C1 200 60 64 - 10 - 1

C2 200 55 69 - 10 - 1

C3 200 60 54 - 20 - 1

C4 200 50 64 - 20 - 1

C5 200 60 44 - 30 - 1

C6 200 45 59 - 30 - 1




Evaluation of Quetiapine Fumarate matrix tablets

All the formulations of Quetiapine Fumarate matrix tablets prepared were evaluated for the

following parameters: [5, 6, 7].

Friability test

Previously weighed 10 tablets were taken in a friabilator and the friability was checked at 25 rpm

for 4 min. Then the tablets were dusted and reweighed and the percentage of powder eroded

during 4 min was recorded. The resulting tablets were weighed and the percentage loss was

calculated using the formula:

Initial weight – Final weight

% Loss = ------------------------------- X 100

Initial weight

Hardness test

Hardness of the tablets was tested using Monsanto hardness tester. In all the cases, means of six

replicate determinations were taken.

Uniformity of drug content

The tablets were powdered and 75 mg equivalent weight of Quetiapine Fumarate in tablet powder

was accurately weighed and transferred into 100ml volumetric flask. Initially 10ml of 6.8 phosphate

buffer was added and shaken for 10min. then volume was made up to100ml.with buffer. The

solution was filtered, and 1ml. of filtrate was diluted and measured at wavelength 290 nm using

double beam UV-Visible spectrophotometer. The drug content of each sample was estimated from

their standard curve.

Weight Variation

Average weight of the tablet was calculated by weighing 20 tablets individually and altogether.

The percent weight deviation of each tablet was computed as per official method1.

Drug polymer interaction studies

(1) IR study: The IR spectrum of Quetiapine fumarate and excipients was recorded to check any

incompatibility between them.

(2) DSC study: DSC spectra of Quetiapine fumarate and Quetiapine fumarate + HPMC K4M +

Tartaric acid was recorded to check any incompatibility between Quetiapine fumarate and HPMC

K4M and Tartaric acid.


S1 200 60 64 - - 10 1

S2 200 55 69 - - 10 1

S3 200 60 54 - - 20 1

S4 200 50 64 - - 20 1

S5 200 60 44 - - 30 1

S6 200 45 59 - - 30 1



In-vitro dissolution studies

Tablets of each formulation were subjected to dissolution studies. In-vitro dissolution studies were

carried out to determine the drug release from various formulations. The release characteristic

studies included the amount of drug released per hour up to 12 hours.

Dissolution medium : 0.1N HCl for 2hr. and 6.8 phosphate buffer for next 8hr.

Dissolution volume : 750ml for 0.1 N HCl then making 1000ml for 6.8 phosphate buffer by addition

of 250 ml of tribasic sodium phosphate.

RPM : 50 RPM

Temperature : 37°C ± 0.5°C

Samples withdrawn : 10ml.

Kinetics of drug release:

To understand the release mechanisms of various formulations of Quetiapine Fumarate, we describe

the rate of release using to zero order (equation 1) and first order (equation 2) kinetics as well as

diffusion controlled mechanism (equation- Higuchi equation 3), Korsmeyer Peppas(eqation 4) .

Q = kot [1]

In (100-Q) = In Qo – k1t [2]

Q = kH t1/2 [3]

Mt /M∞ = k tn [4]

In the above equations, Q is the percentage of drug released at time t and ko, k1t and kH are

coefficients of the equations. Where (Mt /M∞) is the fraction of released drug at time (t), (k) a

characteristic constant of the dosage form and (n) the release exponent, indicative of the drug release

mechanism.

When n is 0.45-0.57, the drug is released from polymer with Fickian diffusion mechanism. If n is

0.57-0.84, the drug is released from polymer with a non Fickian (anomalous) release.

The dissolution profiles of the formulated Quetiapine Fumarate tablets were compared to those of

marketed Quel SR, containing similar amount of Quetiapine Fumarate, using a similarity factor (f2),

described in the following equation:

𝑓2 = 50 × log {[ 1 + (1/n) Rj − Tj

n

j=1

²]¯°˙⁵ × 100}

where n is the sampling number and Rj and Tj are the percentages of dissolved reference and test

products, respectively, at time point j. The Food and Drug Administration (FDA) and the European

Agency for the Evaluation of Medicinal Products (EMEA) suggested that two dissolution profiles

can be declared similar if f2 is between 50 and 100 [8].




Comparison of optimized formula with marketed formulation:

Quel SR tablet 200mg.

Batch no.:B00112002AK

Mfg.by: IPCA Laboratories Ltd.

Mfg.date: Dec. 2012

Exp.date: Nov. 2014

Swelling index:

The swelling index of tablets was determined in mixed phosphate buffer (pH 6.8) at room

temperature. The swollen weight of the tablets was determined at predefined time intervals. The

swelling index was calculated by the following equation:

Where, Wt = Weight of tablet at time t.

W0 = Initial weight of tablet

Stability studies

stability studies were carried out at 400 C and 75% RH for a specific time period up to 90 days for

optimized formulation. For stability study, the tablets were sealed in aluminum packing coated

inside with polyethylene. These sample containers were placed in desiccators maintained at 75%

RH. Formulations after every month studied for friability, hardness and cumulative percentage drug

release.

Optimization using Factorial Design Method (32):

Optimization has been done by using 3² full factorial designs, where concentration of HPMC K4M

(X1) and concentration of Tartaric acid (X2) was taken as independent variables and Cumulative

drug release was taken as dependent variables.

Table No. 2: Factorial Design Batches of Quetiapine Fumarate

Variable Formulations

O1 O2 O3 O4 O5 O6 O7 O8 O9

X1 -1 0 +1 -1 0 +1 -1 0 +1

X2 -1 -1 -1 0 0 0 +1 +1 +1

Table No. 3: Actual and Coded values in the factorial Design


Coded

Values

Actual Values (mg)

X1 X2

-1 40 25

0 45 30

+1 50 35



Optimization Formula:

Optimization of formulation was carried out for following parameters

a. Sustained release of drug

b. pH independent release of drug

This was carried out by studying the effect of different concentration of the polymers and organic

acid.

Table No. 4: Optimization of Formulation batches for HPMC K4M with Tartaric acid

INGREDIENTS Formulations (mg)

O1 O2 O3 O4 O5 O6 O7 O8 O9

Quetiapine

fumarate

200 200 200 200 200 200 200 200 200

HPMC K4M 40 40 40 45 45 45 50 50 50

Dicalcium

phosphate

69 64 59 64 59 54 59 54 49

Tartaric acid 25 30 35 25 30 35 25 30 35

Magnesium stearate 1 1 1 1 1 1 1 1 1

Total 335

mg

335

mg

335

mg

335

mg

335

mg

335

mg

335

mg

335

mg

335

mg

RESULTS AND DISCUSSION

The solubility of the Quetiapine fumarate was found to be

Table No. 5: Solubility data in different solvents

Due to this pH dependent solubility a remarkable difference in the resulting drug release from

HPMC tablet was observed in 0.1 N HCl and in Phosphate buffer pH 6.8 solutions.

In preliminary trail batches the the HPMC conc. and organic acid was found to be in the range of 40-

60 mg and 10-30mg respectively. Hence with these conc. proceeds for further formulations.


SOLVENT SOLUBILITY IN

mg/ml

TERMS

Water 3.3 Slightly soluble

0.1 N HCl 35.6 Soluble

pH 4.5 acetate

buffer

5.8 Slightly soluble

6.8 pH Phosphate

buffer


pH 7.4 phosphate

buffer




Drug: Excipient compatibility study:

(1) IR study: After IR study it was found that there is no change in major peak of drug hence all

Excipients and polymer are compatible with drug. The wavelengths are given in following Table No

Figure No. 1: FTIR Spectra of Quetiapine Fumarate

Figure No. 2: FTIR Spectra of Quetiapine Fumarate + HPMC K4M

Figure No. 3: FTIR Spectra of Succinic acid and Quetiapine fumarate.

Figure No. 4: FTIR Spectra of Tartaric acid and Quetiapine fumarate.

Figure No. 5: FTIR Spectra of Citric acid and Quetiapine fumarate




Figure No. 6: FTIR Spectra of Dicalcium phosphate and Quetiapine fumarate.

Table No. 6: Characteristic IR absorption peaks of functional groups in Drug

Sr. No. Characteristic Peaks cm-1

Characteristic Functional Group

1 3322.75 (3200-3400) O-H

2 3075.9 (3000-3100) C-H aromatic

3 2365.26 (2200-2400) C=N-

4 2869.5 (2890-2880) C-H stretching

5 1130.08 (1360-1180) C-N bending

6 1413.57 (1400-1000) C-O

(2) Differential Scanning Calorimetry (DSC) analysis:

Differential Scanning Calorimetry studies were carried out using DSC instrument (Mettler 5W 920)

indicated a sharp endothermic peak at 177.83°C for melting point of Quetiapine fumarate. The DSC

Spectra of Optimized Formulation with HPMC K4M the peak observed at 184.62 Both DSC spectra

indicates sharp melting point of drug as well as polymer. Hence there is no significant interaction

between drug and polymer.

Figure No. 7: DSC Spectra of Quetiapine Fumarate

Figure No. 8: DSC Spectra of Optimized Formulation with HPMC K4M




EVALUATION OF POWDER BLEND:

Table No. 7: Evaluation of different formulations of powder blend:

Batch Bulk density

(gm/cm3)

Tap density

(gm/cm3)

Carr’s index Hausner’s ratio Angle of repose

F0 0.512±0.09 0.575±0.15 10.95±0.12 1.12±0.09 26.28±0.12

T1 0.530±0.10 0.598±0.12 11.37±0.11 1.12±0.16 26.97±0.10

T2 0.570±0.07 0.616±0.14 7.46±0.18 1.08±0.10 27.33±0.15

T3 0.578±0.12 0.620±0.18 6.77±0.09 1.07±0.09 29.94±0.22

T4 0.425±0.15 0.485±0.15 12.37±0.14 1.14±0.07 22.92±0.19

T5 0.470±0.12 0.502±0.13 6.37±0.13 1.06±0.14 23.21±0.16

T6 0.417±0.03 0.481±0.09 13.30±0.09 1.15±0.12 21.12±0.17

C1 0.421±0.06 0.478±0.07 11.93±0.16 1.13±0.09 22.24±0.16

C2 0.445±0.05 0.487±0.06 8.62±0.09 1.09±0.19 21.22±0.21

C3 0.450±0.08 0.492±0.15 8.53±0.17 1.10±0.13 23.10±0.09

C4 0.417±0.13 0.455±0.17 8.35±0.16 1.09±0.19 23.20±0.18

C5 0.438±0.18 0.485±0.09 9.63±0.11 1.10±0.15 24.38±0.19

C6 0.217±0.14 0.231±0.14 6.06±0.09 1.06±0.17 24.35±0.16

S1 0.228±0.13 0.250±0.09 8.80±0.16 1.09±0.18 24.98±0.08

S2 0.252±0.09 0.290±0.06 13.10±0.17 1.15±0.16 25.05±0.09

S3 0.260±0.08 0.318±0.07 18.23±0.08 1.22±0.17 25.60±0.14

S4 0.295±0.12 0.310±0.19 8.83±0.09 1.05±0.13 23.45±0.17

S5 0.298±0.18 0.330±0.16 9.63±0.13 1.10±0.17 23.95±0.16

S6 0.315±0.09 0.346±0.21 8.95±0.12 1.194±0.15 23.19±0.19

n =3, no. of experiments conducted

The granules of different formulations were evaluated for angle of repose, bulk density, tapped

density, compressibility index and drug content.




EVALUATION OF TABLETS:

Table No. 8: Evaluation result of different tablet formulations:

Batch Thickness

(mm)

Hardness

(kg/cm2)

Weight

Variation(mg)

Friability

(%)

Drug content

F0 3.33± 0.03 5.8± 0.20 334.01± 0.08

0.75

98.91± 0.03

T1 3.32± 0.04 5.9± 0.15

335.04± 0.16

0.78

98.90± 0.05

T2 3.32± 0.01

5.5± 0.16

334.98± 0.05

0.72

98.85± 0.04

T3 3.31± 0.04

5.7± 0.12

334.99± 0.06

0.74

101.18± 0.05

T4 3.32± 0.03

5.9± 0.14

334.98± 0.09

0.72

99.05± 0.06

T5 3.34± 0.02

5.8± 0.22

333.97± 0.10

0.71

98.55± 0.02

T6 3.34± 0.02

4.3± 0.23

335.01± 0.13

0.80

99.97± 0.04

C1 3.33± 0.05

4.4± 0.24

334.00± 0.14

0.81

98.99± 0.02

C2 3.32± 0.06

4.5± 0.15

334.90± 0.15

0.85

96.68± 0.04

C3 3.32± 0.07

4.6± 0.18

333.98± 0.12

0.89

97.18± 0.05

C4 3.31± 0.03

4.9± 0.14

335.08± 0.17

0.88

97.78± 0.02

C5 3.34± 0.05

4.8± 0.23

334.08± 0.14

0.89

98.68± 0.01

C6 3.32± 0.03

6.1± 0.27

333.99± 0.10

0.69

99.98± 0.07

S1 3.30± 0.05

6.1± 0.26

334.98± 0.10

0.68

97.18± 0.09

S2 3.29± 0.01

6.4± 0.20

333.97± 0.09

0.62

97.88± 0.10

S3 3.34± 0.03

6.3± 0.23

334.97± 0.17

0.65

97.01± 0.03

S4 3.32± 0.06

6.2± 0.12

335.05± 0.14

0.65

99.85± 0.04

S5 3.32± 0.03

6.3± 0.20

334.99± 0.15

0.64

99.88± 0.03

S6 3.32± 0.04

6.4± 0.26

333.00± 0.09

0.62

99.01± 0.05

n =3, no. of experiments conducted

The tablets of different formulations were subjected to various evaluation tests, such as thickness,

uniformity of weight, drug content, hardness, friability and in vitro dissolution.




DRUG RELEASE PROFILE:

Dissolution data of matrix tablets are reported in following table. Dissolution study for each

formulation was carried out in triplicate.

In vitro Drug Release Profile of formulation Batches without organic acid

Effect of pH of dissolution media:

There was remarkable difference in the release of Quetiapine Fumarate from HPMC-based matrices

containing no organic acid (F0) in 0.1 N HCl and pH buffer medium of pH 6.8. It is evident that the

drug releases decreased by increase in the pH of the media and after 4 hrs about 53.74 and 41.56 %

of the drug at pH of 1.2 and 6.8 was released respectively. This phenomenon is due to different

solubility of Quetiapine Fumarate as a weak basic drug at pH 1.2 and pH 6.8

The drug release rate at pH 1.2 was increased after about 4 hours when the dissolution experiment

was started. It is probable that the hydrophilic matrix has been completely hydrated at that time and

the glassy core has been disappeared. Therefore a sudden increase in matrix area occurs, which in

turn enhances the rate of the drug release. It seems that matrix erosion become evident at this point.

Regarding the dissolution profile at pH 6.8, this phenomenon might have happened at the late time

of the release study, but it could not compensate the low solubility of Quetiapine Fumarate in order

to increase the dissolution rate [3, 4].

Figure No. 9: Effect of pH on drug release profile of formulation F0 without organic acid

In vitro Drug Release Profile of various formulation Batches

Formulation batches from T1 to T5, C1 to C2 and S1 to S5 were taken with HPMC K4M and tartaric

acid, citric acid, succinic acid at various concentrations.


0

10

20

30

40

50

60

70

80

90

100

0 0.5 1 1.5 2 3 4 5 6 7 8

Cu

mm

ula

tive

% D

rug

Re

leas

e

Time (hr)

F0- 6.8 Buffer

F0- 0.1 N HCl



Figure No. 10: Drug release profile of formulation batches with different organic acid

From above figure the tartaric acid containing batches showed more release than succinic acid and

citric acid within 10 hrs. The comparative release profile was found to be - Tartaric acid > Citric

acid > Succinic acid. Tartaric acid shows more pH-independent release profile for Quetiapine

Fumarate which could be attributed to a variety of factors. The pKa is one of the important factors.

The pKa of tartaric, citric and succinic acid are 2.93, 3.13 and 4.2 respectively. The lower pKa of

tartaric acid can more reduce the pH of microenvironment and improve the solubility and dissolution

of Quetiapine Fumarate at higher pH. Solubility of the organic acids seems to be another factor in

the achievement of desirable release profiles. The order of solubility for three organic acids which

were used in this study is tartaric acid > citric acid > succinic acid (solubility in water:

133gm/100ml, 73gm/100ml and 58gm/100ml respectively). More soluble tartaric acid was the

suitable organic acid in obtaining pH independent release. The freely soluble compounds might

diffuse very rapidly through the polymeric matrices, while fairly soluble acids diffuse out at

relatively lower rate. The similarity factor for T6, C6, S6 was found to be 71.01, 54.28, 49.33

respectively. Formulation T6 was found more similar to the marketed formulation. Hence

formulation T6 was used for formulation of optimize batch [1, 2, 3].


0

10

20

30

40

50

60

70

80

90

100

T1 T2 T3 T4 T5 T6 C1 C2 C3 C4 C5 C6 S1 S2 S3 S4 S5 S6

Cu

mu

lati

ve %

Dru

g R

ele

ase

Formulation Batches



Optimazation of formulation batches from O1 to O9:

Figure No. 11: Drug release profile of Optimization of Formulation batches for HPMC K4M

with Tartaric acid

From above observation the formulation O3 containing 35mg tartaric acid and 40mg HPMC shows

more release profile than other formulations. Because it contains the higher amount of tartaric acid

which gives the more formation of pores on swellable matrix system and erosin of matrix system.

The low amount of HPMC K4M gives the less gel formation around tablet so less chances of closed

pores due to swelling hydrogel. The similarity factor was found in the range of 55.2 - 83.6.

Formulation O3 was found more similar to the marketed formulation. (Similarity factor =83.6)

ANOVA ANALYSIS

The high value of correlation Coefficient for % Drug Release at 10 hrs indicates a good fit.

The The Model F-value of 98.48 implies the model is significant.

Values of "Prob > F" less than 0.0500 indicate model terms are significant. In this case A, B

are significant model terms. Values greater than 0.1000 indicate the model terms are not

significant. There is only a 0.16% chance that a "Model F-Value" this large could occur due

to noise.

High R-square values suggest that these models are significant. In this case model generated

response parameters are significant. PRESS (Predicted Residual Sum of Squares) is a

measure of how well the model fits each point in the design. Smaller the PRESS statistic, the

better the model fits the data points. Small values for the same in this model show a good fit

of the data points.

The "Pred R-Squared" of 0.9274 is in reasonable agreement with the "Adj R-Squared" of

0.9839.


0

20

40

60

80

100

120

1 2 3 4 5 6 7 8 9 10 11

Cu

mu

lati

ve %

Dru

g R

ele

ase

Time (hrs)

O1

O2

O3

O4

O5

O6

O7

O8

O9



"Adeq Precision" measures the signal to noise ratio. A ratio greater than 4 is desirable. Your

ratio of 28.670 indicates an adequate signal. This model can be used to navigate the design

space.

RESPONSE SURFACE PLOTS

All the data obtained was used to generate 3D plots and contour plots for the responses Y. It was

observed that for Y the concentration of the polymer and concentration of tartaric acid affects the

drug release. It was as shown in figure no. 8.20 and 8.21. The 3D plot for the response Y clearly

reveals that the concentration of HPMC K4M prominently retards the release of quetiapine fumarate

this is because of HPMC K4M performs the work of holding the tablet matrix due to its gelling

property. The concentration of organic acid i.e. tartaric acid also significantly affect on drug release

of Quetiapine Fumarate. The tartaric acid helps to maintain pH in buffer media and forms a pH

independent formulation. Hence from this we can say that the release profile of drug totally depends

on concentration of HPMC K4M and concentration of tartaric acid.

The final equation for response Y was obtained in terms coded factor is as follows

Y = 89.25 - 0.74100X1 + 1.10600X2 - 0.017200X1X2 + 0.011000X12 +5.600000X2

2

Where,

Y: Response of cumulative % drug release.

Figure No. 12: 3D Response Surface Plot Showing Effect of Polymer Concentration on Drug

Release at 10 Hours.




Figure No. 13: Contour plot Showing Effect of Polymer Concentration on Drug

Release at 10 Hours.

As the concentration of HPMC K4M increases the drug release decreases due to matrix swelling

which shows inversely proportional relation. The concentration of tartaric acid increases, the drug

release also increases due to more pores formation and erosion of matrix system which shows

directly proportional relation. Thus from this study we can say that HPMC K4M was good drug

retardant and tartaric acid had best organic acid for pH independent formulation. But optimum

concentrations of both variables showed desired effect in the optimized formulation O3.

Comparison of Optimized and marketed formulation

Figure No. 14: Comparison of optimized formulation (O3) and marketed formulation

The optimize formulation (O3) shows more drug release ability than marketed formulation.

The dissolution profiles of the formulated Quetiapine Fumarate tablets were compared to those of

marketed Quel SR, containing similar amount of Quetiapine Fumarate, using a similarity factor (f2),


0

20

40

60

80

100

120

0 1 2 3 4 5 6 7 8 9 10

Cu

mu

lati

ve %

Dru

g R

ele

ase

Time (hrs)

O3 % DR

Marketed formulation % DR



described in the following equation:

𝑓2 = 50 × log {[ 1 + (1/n) 𝑅𝑗 − 𝑇𝑗

𝑛

𝑗=1

²]¯°˙⁵ × 100}

where n is the sampling number and Rj and Tj are the percentages of dissolved reference and test

products, respectively, at time point j.

The Food and Drug Administration (FDA) and the European Agency for the Evaluation of

Medicinal Products (EMEA) suggested that two dissolution profiles can be declared similar if f2 is

between 50 and 100 and it was found to be 83.6 [8].

Swelling index:

Table No. 9: Swelling index of optimized formulations O3 in 6.8 pH buffers, (±SD), n=3.

Time

(hrs)

Weight of tablet (wo) mg Weight of tablet after time (wt)mg % swelling

O3 O3

1 335±0.22 410±0.94 22.38±0.81

2 334± 0.82

470±0.75 40.26±1.22

4 334± 0.73

547±1.22 63.31±0.78

8 333± 1.07

660± 1.02 97.01±0.53

10 334± 0.96 605±0.69 80.59±0.71

Figure No. 15: swelling index in 6.8 pH buffer

The swelling and erosion behaviour of the optimized matrix tablet in 0.1 N HCl (2hrs) and in

phosphate 6.8 pH buffer (later on), as a function of time. The tablets achieved maximum swelling at

8 hr, above which the swelling values goes on decreasing and erosion predominates the release of

the drug from the matrices. Constant release can be obtained from such hydrophilic systems because

of simultaneous swelling and erosion of the matrix tablets.


0

20

40

60

80

100

120

1 2 4 8 10

% S

we

llin

g

Time (hrs)



Stability study:

Table No. 10: Physical evaluation parameters of formulation O3 during stability study

Sampling

Time

Interval

(Months)

Thickness

(mm)

Hardness

(kg/cm2)

Weight

Variation(mg)

Friability

(%)

Drug content

1 3.32± 0.04

5.9± 0.15

335.56± 0.12

0.80

99.05± 0.06

2 3.32± 0.03

5.5± 0.16

334.97± 0.10

0.71

98.55± 0.02

3 3.32± 0.02

5.7± 0.12

334.01± 0.13

0.78

97.97± 0.04

All values are mean ± SD, (n=3)

Table No. 11: Stability of O3 for 3 months, (±SD), n=3.

Time

(hrs)

O3 % DR O3 after

1 month

O3 after

2 month

O3 after

3 month

0 0 0 0 0

1 18.2±1.22 18.1±0.97 17.9±0.74 17.2±0.78

2 25.7±1.69 24.7±0.86 24.1±1.18 23.6±1.45

3 41.5±1.56 41.3±1.27 40.8±0.59 40.5±1.26

4 60.9±1.88 59.8±0.79 59.1±0.86 58.7±1.35

5 70±1.39 69.7±1.17 69.2±1.14 68.9±1.28

6 75.8±0.97 74.8±0.84 74.5±1.21 74.2±0.93

7 80.9±1.76 80.7±1.32 80.1±1.45 79.9±0.87

8 89.6±1.39 88.9±0.97 88.6±0.91 88.1±0.90

9 92.9±1.22 92.7±0.65 92.1±0.88 91.9±1.07

10 97.9±1.57 96.8±0.48 96.5±1.40 95.9±0.33

Figure No. 16: Dissolution profiles of formulation O3 during stability study


0

20

40

60

80

100

120

0 1 2 3 4 5 6 7 8 9 10

Cu

mu

lati

ve %

Dru

g R

ele

ase

Time (hrs)

O3 % DR

O3 after 1 month

O3 after 2 month

O3 after 3 month



Result of accelerated stability study of optimized formulations O3 indicated that physical changes

were not observed in the samples at the time intervals of 1 month, 2 month and 3 months. Weight of

tablet, thickness, Hardness, drug content uniformity, and dissolution profiles were unaffected during

stability study. Formulation O3 showed % drug release of 95.9 % at the end of 10 hrs, after 3

months, which proved that dissolution profile of Quetiapine Fumarate was not affected during

stability study. Hence, formulations O3 was found to be stable during accelerated stability study.

SUMMARY AND CONCLUSION:

The formulation containing tartaric acid showed better release than citric acid and succinic acid. It

seems that lower pKa of tartaric acid results in a pH-independent drug release profile. The solubility

of organic acid as well as the type of matrix former showed also be consider as two other important

aspects in achievement of appropriate result.

REFERENCES:

1. Bolourchian N, Dadashzadeh S, (2008), pH-independent release of propranolol

hydrochloride from HPMC based matrices using organic acids, DARU Journal of

Pharmaceutical Sciences, Vol. 16(3), 136-142.

2. Jayanthi, (2011), pH independent controlled release swellable matrix tablets., International

Journal of Research in Ayurveda and Pharmacy, Vol 2(2), 577-580.

3. Kumud Kumar Padhy, (2010), Influence of organic acids on drug release pattern of

verapamil hydrochloride pellets, Journal of Advanced Pharmaceutical Research, Vol 1, 65-

73.

4. Deepak Sahu, (2010), Development and in vitro evaluation of Quetiapine Fumarate Sustain

release tablets, International Journal of Pharm Tech Research, Vol 2(4), 2535-2543.

5. Sanjay Kshirsagar, (2012), Formulation and evaluation of matrix-based sustained release

tablets of quetiapine fumarate and the influence of excipients on drug release., Journal of

chemical and pharmaceutical research, Vol 4(6), 3073-3081

6. Pallavi A. Kadam, Dr. Parag V. Jain, (2012), Formulation and evaluation of sustained release

matrix tablet of quetiapine fumarate, IJPRD, Vol 4(0), 324 – 331.

7. Mohd Khaja Pasha, G.Velrajan, (2013), Formulation and evaluation of extended release

matix tablets of quetiapine fumarate tablets, International journal of pharmacy, Vol 3(1), 14-

19.

8. Costa P, Lobo JM, (2001), A review on modeling and comparison of dissolution profiles,

European journal of pharmaceutical sciences, Vol 13, 123-133.



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