international standard serial number (issn): 2319-8141 .... rpa131400180.pdf · mt /m∞ = k tn [4]...
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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-
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.
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International Standard Serial Number (ISSN): 2319-8141
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
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International Standard Serial Number (ISSN): 2319-8141
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.
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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
International Standard Serial Number (ISSN): 2319-8141
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].
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International Standard Serial Number (ISSN): 2319-8141
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
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Coded
Values
Actual Values (mg)
X1 X2
-1 40 25
0 45 30
+1 50 35
International Standard Serial Number (ISSN): 2319-8141
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.
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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
2.1 Slightly soluble
pH 7.4 phosphate
buffer
1.3 Slightly soluble
International Standard Serial Number (ISSN): 2319-8141
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
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International Standard Serial Number (ISSN): 2319-8141
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
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International Standard Serial Number (ISSN): 2319-8141
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.
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International Standard Serial Number (ISSN): 2319-8141
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.
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International Standard Serial Number (ISSN): 2319-8141
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.
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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
International Standard Serial Number (ISSN): 2319-8141
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].
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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
International Standard Serial Number (ISSN): 2319-8141
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.
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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
International Standard Serial Number (ISSN): 2319-8141
"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.
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International Standard Serial Number (ISSN): 2319-8141
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),
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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
International Standard Serial Number (ISSN): 2319-8141
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.
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0
20
40
60
80
100
120
1 2 4 8 10
% S
we
llin
g
Time (hrs)
International Standard Serial Number (ISSN): 2319-8141
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
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20
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60
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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
International Standard Serial Number (ISSN): 2319-8141
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.
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1. Bolourchian N, Dadashzadeh S, (2008), pH-independent release of propranolol
hydrochloride from HPMC based matrices using organic acids, DARU Journal of
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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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